Thiochromenones used to combat painful conditions and neurodegenerative diseases

ABSTRACT

The invention relates to novel thiochromenones and processes for their preparation, to their use for the treatment and/or prophylaxis of diseases, especially for the treatment and/or prophylaxis of states of pain and neurodegenerative disorders.

The invention relates to novel thiochromenones and processes for theirpreparation, to their use for the treatment and/or prophylaxis ofdiseases, especially for the treatment and/or prophylaxis of states ofpain and neurodegenerative disorders.

The amino acid L-glutamate is the principal excitatory neurotransmitterin the brain. Glutamate receptors can be divided into two largeclasses: 1. ionotropic receptors which control ion channels directly,and 2. metabotropic receptors (mGluRs).

Metabotropic glutamate receptors are a heterogeneous class of Gprotein-coupled receptors which, activated by glutamate, are able toactivate various second messenger cascades. The second messengercascades culminate in the modulation of numerous intracellularprocesses, including regulation of presynaptic glutamate release andregulation of postsynaptic ionotropic glutamate receptors.

At present, 8 different. subtypes of metabotropic glutamate receptorsdiffering in second messenger cascade, pharmacology and localization inthe brain are known (review: Ann. Rev. Pharnacol. Toxicol. 1997, 37,205).

U.S. Pat. No. 4,221,800 and U.S. Pat. No. 4,571,405 describe theantiallergic effect of thioxanthen-9-ones.

The preparation and the antischistosomal effect of thioxanthen-9-onesand 2,3-cyclopentathiochromones are disclosed in U.S. Pat. No.3,312,598, GB 803,803, GB 804,689, GB 805,870, Chem. Abstr. 54, 7740d(DE 1024981), Chem. Abstr. 62, 11763h and J. Med. Chem. 1967, 10,867-876.

The synthesis of2-chloro-6,7,8,9,10,10a-hexahydrocyclohepta[b]thiochromen-11(5aH)-one isdescribed in Liebigs Ann. 1964,680,40-51.

2,3-Cyclopentathiochromones are disclosed as analgesics andantiinflanmatory agents in CAPLUS 1984, 610989 (JP 59112983).

The present invention relates to compounds of the general formula (I)

-   -   in which    -   the radical R¹-A- is located at either of positions 2 or 3 of        the thiochromenone ring,    -   R¹ is (C₆-C₁₀)-aryl or 5- to 10-membered heteroaryl, where aryl        and heteroaryl are optionally substituted identically or        differently by radicals selected from the group of halogen,        formyl, carbamoyl, cyano, hydroxyl, trifluoromethoxy, nitro,        —NR³R⁴, tetrazolyl, (C₁-C₆)-alkoxycarbonyl and optionally        hydroxyl-, morpholinyl-, (C₁-C₆)-acyloxy- or halogen-substituted        (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₁-C₆)-acyl and        (C₁-C₆)-alkylthio,        -   in which        -   R³ and R⁴ are, independently of one another, hydrogen,            (C₁-C₆)-alkyl or (C₁-C₆)-acyl,            -   is 3- to 12-membered carbocyclyl or 4- to 12-membered                heterocyclyl, where carbocyclyl and heterocyclyl are                optionally substituted identically or differently by                radicals selected from the group of (C₁-C₆)-alkyl,                (C₁-C₆)-alkoxy, (C₁-C₆)-acyl, (C₁-C₆)-alkoxycarbonyl or                oxo,        -   or        -   is a group of the formula R⁵-E-,        -   in which        -   E is optionally unsaturated (C₁-C₁₀)-alkanediyl, and        -   R⁵ is hydrogen, carbamoyl, halogen, hydroxyl, nitro,            trifluoromethyl, amino, mono-(C₁-C₆)-alkylamino,            di-(C₁-C₆)-alkylamino, (C₁-C₆)-alkoxy, (C₆-C₁₀)-aryl, 5- to            10-membered heteroaryl or 4- to 10-membered, optionally oxo-            and/or (C₁-C₆)-alkyl-substituted, optionally benzo-fused            heterocyclyl, where aryl, heteroaryl and benzo in turn may            be substituted by radicals selected from the group of            halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro and            (C₁-C₆)-alkyl,    -   A is a bond or a group of the formula O, S, NR⁶, CO, SO, SO₂,        SO₂—O, CO—NR⁷, SO₂—NR⁸, O—SO₂, NR⁹—CO, NR¹⁰—SO₂, NR¹¹—SO₂—O,        NR¹²—SO₂—NR¹³ or NR⁴—CO—NR¹⁵,        -   in which        -   R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ are            (C₃-C₈)-cycloalkyl or optionally unsaturated (C₁-C₆)-alkyl            which is optionally substituted by hydroxyl, phenyl,            (C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl or            (C₃-C₈)-cycloalkyl, where phenyl in turn may be substituted            by halogen or (C₁-C₄)-alkyl, or    -   in which        -   R⁶, R⁷, R⁹, R¹⁰, R¹¹, R¹², R¹⁴and R⁵ are hydrogen,    -   or    -   the radical R¹-A- is hydrogen or ammo,    -   R² is hydrogen, halogen or (C₁-C₆)-alkyl or (C₁-C₆)-alkoxy,        where alkyl and alkoxy are optionally substituted up to twice        identically or differently by radicals selected from the group        of hydroxyl, (C₁-C₆)-alkoxy, mono- and di-(C₁-C₆)-alkylamino,        and    -   D is an optionally fluorine-substituted, divalent hydrocarbon        radical having 3 to 10 carbon atoms,    -   and the salts, hydrates and/or solvates thereof,    -   with the exception of        2-chloro-6,7,8,9,10,10a-hexahydrocyclohepta[b]thiochromen-11(5aH)-one.

The compounds of the invention may exist in stereoisomeric forms whicheither are related as image and mirror image (enantiomers) or which arenot related as image and mirror image (diastereomers). The inventionrelates both to the enantiomers or diastereomers or respective mixturesthereof. These mixtures of enantiomers and diastereomers can beseparated in a known manner into the stereoisomerically pureconstituents.

The compounds of the invention may also exist in the form of theirsalts, hydrates and/or solvates.

Salts which are preferred for the purposes of the invention arephysiologically acceptable salts of the compounds of the invention.

Physiologically acceptable salts of the compounds of the invention maybe acid addition salts of the compounds with mineral acids, carboxylicacids or sulfonic acids. Particularly preferred examples are salts withhydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid,benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionicacid, lactic acid, tartaric acid, citric acid, flimaric acid, maleicacid or benzoic acid.

Salts which may also be mentioned, however, are salts with conventionalbases such as, for example, alkali metal salts (e.g. sodium or potassiumsalts), alkaline earth metal salts (e.g. calcium or magnesium salts) orammonium salts derived from ammonia or organic amines such as, forexample, diethylamine, triethylamine, ethyldiisopropylairune, procaine,dibenzylamine, N-methylmorpholine, dihydroabietylarnine, 1-ephenamine ormethylpiperidine.

Hydrates of the compounds of the invention are stoichiometriccompositions of the compounds or its salts with water.

Solvates of the compounds of the invention are stoichiometriccompositions of the compounds or its salts with solvent.

For the purposes of the present invention, the substituents generallyhave the following meaning:

(C₁-C₆)-Acyl is a straight-chain or branched acyl radical having 1 to 6carbon atoms. Examples which may be mentioned are: acetyl,ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl,pivaloyl, isobutylcarbonyl, pentylcarbonyl and hexylcarbonyl. Astraight-chain or branched acyl radical having 1 to 4 carbon atoms ispreferred. Acetyl and ethylcarbonyl are particularly preferred.

(C₁-C₁₀)-Alkanediyl is a straight-chain or branched alkanedjyl radicalhaving 1 to 10 carbon atoms, it being possible for the two freevalencies of the alkanediyl radical to be on one carbon atom (geminal),on adjacent carbon atoms (vicinal) or on nonadjacent carbon atoms. Astraight-chain or branched alkanediyl radical having 3 to 8,particularly preferably having 3 to 6, carbon atoms is preferred.Examples which may be mentioned are methylene, ethylene, propylene,propane-1,2-diyl, propane-2,2-diyl, 2-methylpropane-1,3-diyl,butane-1,3-diyl, butane-2,4-diyl, pentane-2,4-diyl,2-methylpentane-2,4-diyl.

(C₁-C₆)-Alkoxy is a straight-chain or branched alkoxy radical having 1to 6 carbon atoms. A straight-chain or branched alkoxy radical having 1to 4 carbon atoms is preferred. Examples which may be mentioned are:methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy andn-hexoxy. A straight-chain or branched alkoxy radical having 1 to 3carbon atoms is particularly preferred.

(C₁-C₆)-Alkoxycarbonyl is a straight-chain or branched alkoxycarbonylradical having 1 to 6 carbon atoms. A straight-chain or branchedalkoxycarbonyl radical having 1 to 4 carbon atoms is preferred. Exampleswhich may be mentioned are: methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl. Astraight-chain or branched alkoxycarbonyl radical having 1 to 3 carbonatoms is particularly preferred.

(C₁-C₆)- and (C₁-C₃)-alkyl is a straight-chain or branched alkyl radicalhaving, respectively, 1 to 6 and 1 to 3 carbon atoms. A straight-chainorbranched alkyl radical having 1 to 4, particularly preferably having 1to 3, carbon atoms is preferred. Examples which may be mentioned are:methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

(C₁-C₆)-Alkylamino is a straight-chain or branched alkylamino radicalhaving 1 to 6 carbon atoms. A straight-chain or branched alkylaminoradical having 1 to 4 carbon atoms is preferred. Examples which may bementioned are: methylamino, ethylamino, n-propylamino, isopropylamino,tert-butylamino, n-pentylamino and n-hexylamino. A straight-chain orbranched alkylamino radical having 1 to 3 carbon atoms is particularlypreferred.

(C₁-C₆)-Dialkylamino is a straight-chain or branched dialkylaminoradical, where the alkyl radicals may be identical or different and eachcontain 1 to 6 carbon atoms. A straight-chain or branched dialkylaminoradical is preferred, with the alkyl radical containing in each case 1to 4 carbon atomns. Examples which may be mentioned are: dimethylamino,diethylamino, di-n-propylamino, diisopropylarino, di-t-butylamino,di-n-pentylamino, di-n-hexylamino, ethylmethylammno,isopropylmethylamino, n-butylethylamino, n-hexyl-i-pentylamino. Astraight-chain or branched alkylamino radical having 1 to 3 carbon atomsis particularly preferred.

(C₁-C₆)-Alkylthio is a straight-chain or branched alkylthio radicalhaving 1 to 6 carbon atoms. A straight-chain or branched alkylthioradical having 1 to 4 carbon atoms is preferred. Examples which may bementioned are: methylthio, ethylthio, n-propylthio, isopropylthio,tert-butylthio, n-pentylthio and n-hexylthio. A straight-chain orbranched alkylthio radical having 1 to 3 carbon atoms is particularlypreferred.

(C₆-C₁₀)-Aryl is generally an aromatic radical having 6 to 10 carbonatoms. Preferred aryl radicals are phenyl and naphthyl.

3- to 12-membered carbocyclyl is a mono- or polycyclic, carbocyclicradical having 3 to 12 nirng atoms. 3- to 10-membered, in particular 3-to 8-membered, carbocyclyl are preferred. Mono- or bicyclic carbocyclylis preferred. Monocyclic carbocyclyl is particularly preferred. Thecarbocyclyl radical may be saturated or partially unsaturated. Saturatedcarbocyclyi radicals are preferred. Likewise preferred are(C₃-C₁₀)-cycloalkyl, very particularly (C₄-C₇)-cycloalkyl. Exampleswhich may be mentioned are: cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cycloheptyl, norbom-1-yl, norbom-2-yl,norbom-7-yl, norbom-2-en-7-yl, cyclooctyl, cubyl, cyclononyl,cyclodecyl, decalinyl, adamant-1-yl, adamant-2-yl.

(C₃-C₈)-Cycloalkane-1,1-diyl is cyclopropane-1,1diyl,cyclobutane-1,1-diyl, cyclopentane-1,1-diyl or cyclohexane-1,1-diyl.

(C₃-C₈)-Cycloalkyl is cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl,cycloheptyl or cyclooctyl. The following may be mentioned as preferred:cyclopropyl, cyclopentyl and cyclohexyl.

Halogen is fluorine, chlorine, bromine and iodine. Fluorine, chlorineand bromine are preferred. Fluorine and chlorine are particularlypreferred.

5- to 10-membered heteroaryl is an aromatic, mono- or bicyclic radicalhaving 5 to 10 ring atoms and up to 5 heteroatoms from the series S, Oand/or N, 5- to 6-membered heteroaryls having up to 4 heteroatoms arepreferred. The heteroaryl radical may be bonded via a carbon atom orheteroatom. Examples which may be mentioned are: thienyl, furyl,pyrrolyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, pyridyl,pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl,benzothiophenyl, quinolinyl, isoquinolinyl.

4- to 12-membered or 4- to 10-membered heterocvclvi is a mono- orpolycyclic, heterocyclic radical having, respectively, 4 to 12 or 10ring atoms and up to 4, preferably up to 2, heteroatoms or hetero groupsfrom the series N, O, S, SO, SO₂. 4- to 8-membered heterocyclyl ispreferred. Mono- or bicyclic heterocyclyl is preferred. Monocycliccarbocyclyl is particularly preferred. N and O are preferred asheteroatoms. The heterocyclyl radicals may be saturated or partlyunsaturated. Saturated heterocyclyl radicals are preferred. Theheterocyclyl radicals may be bonded via a carbon atom or a heteroatom.5- to 7-membered, monocyclic saturated heterocyclyl radicals having upto two heteroatoms from the series O, N and S are particularlypreferred. Examples which may be mentioned are: oxetan-3-yl,pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, tetrahydrofuranyl,tetrahydrothienyl, pyranyl, piperidinyl, piperazinyl, thiopyranyl,morpholinyl, perhydroazepinyl, 1,5-dioxa-9-azaspiro[5,5]undecyl.

A divalent hydrocarbon radical having 3 to 10 carbon atoms is astraight-chain, branched, partly cyclic or cyclic, saturated orunsaturated organic radical which comprises 3 to 10 carbon atoms, whichis linked via two bonds on one or two carbon atoms of the hydrocarbonradical to the adjacent atoms and which is saturated at the freevalencies, depending on the degree of saturation and cyclization, withhydrogen atoms. Saturated organic radicals are preferred. Likewisepreferred are hydrocarbon radicals having 3 to 8, particularlypreferably having 3 to 6, carbon atoms. The hydrocarbon radical mayconsist of a straight-chain or branched alkanediyl radical, in whichcase two geminal, vicinal or nonadjacent hydrogen atoms of thealkanediyl radical may in turn be replaced by a straight-chain orbranched alkanediyl radical. Examples which may be mentioned are:straight-chain or branched (C₃-C₁₀)-alkanediyl,(C₃-C₁₀)-cycloalkanediyl, and, with a total of 3 to 10 carbon atoms,mono- or dialkylcycloalkanediyl, cycloalkylalkanediyl,(yloalkyl)cycloalkyl, (ylocycloalkyl)alkyl and[(yloalkyl)cycloalkyl]alkyl. Examples which may be mentioned are:propylene, butylene, pentylene, butane-1,2-diyl,2-ethylpropane-1,3-diyl, 2-methylethane-1,2-diyl,2-methylpropane-1,2-diyl, 2-methylbutane-1,3-diyl, cyclobutane-1,1-diyl,cyclopentane-1,1-diyl, cyclohexane-1,1-diyl, cyclohexane-1,2-diyl,cyclohexane-1,3-diyl, 4,4-dimethylcyclohexane-1,1-diyl,4-tert-butyl-cyclohexane-1,1-diyl, 2-cyclohexylpropane-1,3-diyl,1-ylomethylcyclobutyl, 1-ylomethylcyclohexyl, 1-(2-yloethyl)cyclohexyl,2-(2-yloethyl)cyclohexyl, [1-(ylomethyl)cyclobut-1-yl]methyl,[1-(ylomethyl)cyclohex-1-yl]methyl.

Oxo is a doubly bonded oxygen atom.

If radicals in the compounds of the invention are optionallysubstituted, the radicals may be substituted one or more times,identically or differently, unless specified otherwise. Substitution byup to three identical or different substituents is preferred.

If radicals in the. compounds of the invention are optionallyunsaturated, the radical comprises, unless specified otherwise, one ormore double or triple bonds which are optionally in conjugated orcumulative form. Double bonds are preferred. One double bond isparticularly preferred.

One embodiment of the invention relates to compounds of the generalformula (I),

in which the radical R¹-A- is located at position 3, the radical R² islocated at position 2 of the thiochromenone ring, and R¹, A, R² and Dhave the meaning indicated above.

A further embodiment of the invention relates to compounds of thegeneral formula (I),

-   in which-   the radical R¹-A- is located at position 3 of the thiochromenone    ring,-   R¹ is (C₆-C₁₀)-aryl or 5- to 10-membered heteroaryl, where aryl and    heteroaryl are optionally substituted identically or differently up    to twice by radicals selected from the group of halogen, formyl,    cyano, hydroxyl, hydroxymethyl, (C₁-C₆)-alkyl,    -   is 4- to 10-membered heterocyclyl, where heterocyclyl are        optionally substituted identically or differently by radicals        selected from the group of (C₁-C₆)-alkyl, (C₁-C₆)-alkoxY,        (C₁-C₆)-alkoxycarbonyl or oxo,-   A is a bond or a group of the formula NR⁶, CO-Nk⁷, SO₂—NR⁸ or    NR⁹—CO,    -   in which    -   R⁶, R⁷, R⁸ and R⁹ are hydrogen or optionally unsaturated        (C₁-C₆)-alkyl which is optionally substituted up to twice,        identically or differently, by hydroxyl or methoxy, or    -   in which    -   R⁶, R⁷ and R⁹ are hydrogen,-   R² is hydrogen, and-   D is a group of the formula (CH₂)_(m)—CR¹⁶R¹⁷—(CH₂)_(n),    -   in which the total number of carbon atoms is 3 to 10,    -   m and n are identical or different and are a natural number from        the series 0 to 6,    -   and    -   R¹⁶ and R¹⁷ are identical or different and are hydrogen or        (C₁-C₆)-alkyl which is optionally substituted identically or        differently by (C₃-C₅)-cycloalkyl or halogen,    -   or    -   CR¹⁶R¹⁷ is (C₃-C₆)-cycloalkane-1,1-diyl,        and the salts, hydrates and/or solvates thereof.

A further embodiment of the invention relates to compounds of thegeneral formula (I),

-   in which-   the radical R¹-A- is located at position 3 of the thiochromenone    ring,-   R¹ is phenyl or 5- to 6-membered heteroaryl, where phenyl and    heteroaryl are optionally substituted identically or differently up    to twice by radicals selected from the group of halogen, cyano,    (C₁-C₃)-alkyl,    -   is 5- to 7-membered heterocyclyl, where heterocyclyl are        optionally substituted identically or differently by radicals        selected from the group of (C₁-C₃)-alkyl or oxo,-   A is a bond or a group of the formula NR⁶, SO₂—NR⁸ or NR⁹—CO,    -   in which    -   R⁶, R⁸ and R⁹ are hydrogen or optionally unsaturated        (C₁-C₃)-alkyl which is optionally substituted up to twice,        identically or differently, by hydroxyl or methoxy, or    -   in which    -   R⁶ and R⁹ are hydrogen,-   R² is hydrogen, and-   D is a group of the formula (CH₂)_(m)—CR¹⁶R¹⁷—(CH₂)_(n),    -   in which    -   the total number of carbon atoms is 3 to 6,    -   m and n are identical or different and are a natural number from        the series 0 to 2,    -   and    -   R¹⁶ and R¹⁷ are identical or different and are hydrogen or        (C₁-C₃)-alkyl,    -   or    -   CR¹⁶R¹⁷ is (C₃-C₆)-cycloalkane-1,1-diyl,        and the salts, hydrates and/or solvates thereof.

A further embodiment of the invention relates to compounds of thegeneral formula (I),

-   in which-   the radical R¹-A- is located at position 3 of the thiochromenone    ring,-   R¹, A and R² have the meaning indicated above, and-   D is 2-methylpropane-1,2-diyl.

A further embodiment of the invention relates to compounds of thegeneral formula (I),

-   in which-   the radical R¹-A- is located at position 3 of the thiochromenone    ring,-   A is CO—NR⁷, SO₂—NR⁸ or NR⁹—CO,    -   in which    -   R⁷, R⁸ and R⁹ have the meaning indicated above,-   R² is hydrogen, and-   R¹ and D have the meaning indicated above.

The invention further relates to processes for preparing the compoundsof the formula (I).

In process

-   [A] compounds of the general formula (II)    -   in which    -   R¹⁸ is located at one of positions 2 or 3 of the thiochromenone        ring,    -   R² and D have the meaning indicated above, and    -   R¹⁸ is bromine or chlorine,    -   are reacted with compounds of the general formula (III)        R¹⁹—BR²⁰R²¹  (III),    -   in which    -   R¹⁹ is (C₆-C₁₀)-aryl or 5- to 10-membered heteroaryl, where aryl        and heteroaryl are optionally substituted identically or        differently by radicals selected from the group of halogen,        formyl, carbamoyl, cyano, hydroxyl, trifluoromethoxy, nitro,        —NR³R⁴, (C₁-C₆)-alkoxycarbonyl and optionally hydroxyl-,        morpholinyl-, (C₁-C₆)-acyloxy- or halogen-substituted        (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₁-C₆)-acyl and        (C₁-C₆)-alkylthio,    -   in which    -   R³ and R⁴ are, independently of one another, hydrogen,        (C₁-C₆)-alkyl or (C₁-C₆)-acyl, and    -   R²⁰ and R²¹ are hydroxyl,    -   or    -   BR²⁰R²¹ is    -   to give compounds of the general formula (Ia)    -   in which    -   R¹⁹ is located at one of positions 2 or 3 of the thiochromenone        ring, and    -   R², R¹⁹ and D have the meaning indicated above,    -   in inert solvents under usual reaction conditions in the        presence of a catalyst (see, for example: J. Tsuji, Palladium        Reagents and Catalysts, J. Wiley & Sons, 1995; Suzuki coupling,        review: N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95,        2457-2483; H. Gröger, J. Prakt. Chem. 2000, 342, 334-339).

Process [A] is preferably carried out under Suzuki reaction conditionswith palladium catalysts usual therefor, examples of particularlypreferred catalysts being dichlorobis(triphenylphosphine)palladium,tetrakistriphenylphosphinepalladium(0), palladium(II) acetate orbis(diphenylphosphaneferrocenyl)palladium(II) chloride.

Suzuki reactions are carried out with usual additional reagents such aspotassium acetate, cesium, potassium or sodium carbonate, bariumhydroxide, potassium tert-butoxide, cesium fluoride or potassiumphosphate, examples of particularly preferred additional reagents beingpotassium acetate and/or aqueous sodium carbonate solution.

Suzuki reactions are carried out in inert solvents which are not changedunder the reaction conditions, and these include ethers such as dioxane,tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons such as benzene,xylene or toluene, or other solvents such as nitrobenzene,dimethylformamide, dimethylacetamide, dimethyl sulfoxide orN-methylpyrrolidone, examples of particularly preferred solvents beingdimethylformamide, dimethylacetamide, dimethyl sulfoxide or1,2-dimethoxyethane.

Process [A] is preferably carried out in a temperature range from roomtemperature to 130° C. under atmospheric pressure.

The compounds (III) are commnerically available or can be prepared byknown methods or can be prepared for the reaction in situ as describedbelow.

The biaryl syntheses which take place via boronates prepared in situ areprepared under usual reaction conditions in the presence of a catalyst,preferably in the presence of a transition metal catalyst, in particularin the presence of a palladium catalyst (see, for example, A. Giroux, Y.Han, P. Prasit, Tetrahedr. Lett. 1997, 38, 3841-44; T. Ishiyama, M.Murata, N. Miyaura, J. Org. Chem. 1995, 60, 7508-10.), preferably indimethylformamide or dimethyl sulfoxide as solvent. The transition metalcatalysts preferably used are palladiurn(0) or palladium(II) compounds,in particular bis(diphenylphosphaneferrocenyl)palladium(II) chloride.The reaction takes place in particular at a temperature from 70° C. to110° C. in the presence of bases, preferably potassium acetate and/oraqueous sodium carbonate solution.

Also used besides Suzuki reactions are aryl coupling reaction withorganotin (Stille coupling) or substituted olefins (Heck reaktion) underthe reaction conditions usual therefor in the presence of a catalyst,preferably in the presence of a transition metal catalyst, in particularin the presence of a palladium catalyst (see, for example, J. Tsuji,Palladium Reagents and Catalysts, J. Wiley & Sons, 1995) preferably indimethylformamide, N-methylpyrrolidone, 1,2-dimethoxyethane or tolueneas solvent at a temperature of 60-140° C. The transition metal catalystspreferably used are palladium(0) or palladium(II) compounds, inparticular bis(triphenylphos-phane)palladium(II) chloride, palladium(II)acetate or tetrakis(triphenylphosphane)-palladium(0). When organotincompounds are used (Stille coupling, review: V. Farina, V.Krishnamurthy, W. J. Scott in: The Stille Reaction, J. Wiley and Sons,New York; 1998), the reaction takes place in particular at a temperaturefrom 110° C. to 130° C. When olefins are used (Heck reaction, review: I.P. Beletskaya, A. V. Cheprakov: The Heck Reaction as a Sharpening Stoneof Palladium Catalysis, Chem. Rev. 2000, 100, 3009-3066.) the reactiontakes place in particular at a temperature of 80-100° C. in the presenceof a base, preferably triethylamine or aqueous sodium bicarbonatesolution, and in the presence of a tetraalkylammonium or phosphoniumsalt, preferably tetrabutylammonium chloride or bromide.

The compounds of the general formula (II) can be prepared from theappropriate precursors for example in analogy to process [M].

The compounds of the general formula (III) are known or can be preparedby known processes.

In process

-   [B] compounds of the general formula (II) are reacted with compounds    of the general formula (IV)    R²²—H  (IV),    -   in which    -   R²² is a 4- to 12-membered heterocyclyl which is bonded via N,        where heterocyclyl comprises at least one nitrogen atom having a        free valency, and is optionally substituted identically or        differently by radicals selected from the group of        (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₁-C₆)-acyl,        (C₁-C₆)-alkoxycarbonyl or oxo,    -   to give compounds of the general formula (Ib)    -   in which    -   R²² is located at one of positions 2 or 3 of the thiochromenone        ring, and    -   R¹, R²² and D have the meaning indicated above,    -   in inert solvents under the conditions usual for such reactions.

In process

-   [C] compounds of the general formula (II) are reacted with compounds    of the general formula (V)    R¹-G-H  (V),    -   in which    -   R¹ has the meaning indicated above, and    -   G is O, S or NR⁶, in which R⁶ has the meaning indicated above,    -   to give compounds of the general formula (Ic)    -   in which    -   R¹-G- is located at one of positions 2 or 3 of the        thiochromenone ring, and    -   R¹, R², D and G have the meaning indicated above,    -   in inert solvents under usual reaction conditions in the        presence of a catalyst.

Processes [B] and [C] are preferably carried out with catalysis bypalladium (S. L. Buchwald, et al., J. Am. Chem. Soc. 1999, 121,4369-4378; J. F. Hartwig, et al., J. Org. Chem. 1999, 64, 5575-5580;Buchwald aminations: J. P. Wolfe, S. L. Buchwald, J. Org. Chem. 2000,65, 1144-1157; J. P. Wolfe, H. Tomori, J. P. Sadighi, J. Yin, S. L.Buchwald, J. Org. Chem. 2000, 65, 1158-1174) or Cu(I) (J. Lindley,Tetrahedron 1984, 40, 1433) examples of particularly preferred catalystsbeing tris(dibenzylideneacetone)dipalladium(0), palladium acetate orcopper(I) iodide.

Processes [B] and [C] are optionally carried out with addition of basessuch as, for example, alkali metal carbonates such as cesium carbonate,sodium or potassium carbonate, or sodium or potassium methanolate, orsodium or potassium methanolate, or sodium or potassium tert-butoxide,or other bases such as potassium phosphate, DBU, pyridine, triethylamineor diisopropylethylamine, examples of particularly preferred bases beingpotassium phosphate, sodium tert-butoxide, potassium carbonate, cesiumcarbonate, triethylamine, diisopropylethylamine or pyridine.

If the reaction is carried out with Pd catalysis, processes [B] and [C]are carried out where appropriate with addition of ligands, examples ofparticularly preferred ligands being 2-(di-t-butylphosphino)biphenyl,triphenylphosphine,[5-(diphenylphosphino)-9,9-dimethyl-9H-xanthen-4-yl](diphenyl)phosphine,1,1′-biphenyl-2-yl(dicyclohexyl)phosphine or(+/−)-2,2-bis(diphenylphosphino)-1,1-binaphthyl.

Processes [B] and [C] are carried out in inert solvents which are notchanged under the reaction conditions, and these include ethers such asdioxane, tetrahydrofuran or 1,2-dimnethoxyethane, hydrocarbons such asbenzene, xylene or toluene, or other solvents such asdimethylformarnide, dimethylacetarnide, pyridine or N-methylpyrrolidone,examples of particularly preferred solvents being toluene, xylene,dimethylformaride, dimethylacetaride or pyridine.

Processes [B] and [C] are preferably carried out in a temperature rangefrom room temperature up to refluxing of the solvents under atmosphericpressure.

The compounds of the general formulae (IV) and (V) are known or can beprepared by known processes.

In process

-   [D] compounds of the general formula (VI)    -   in which    -   H—Y— is located at one of positions 2 or 3 of the thiochromenone        ring,    -   R² and D have the meaning indicated above, and    -   Y is O, S or NR⁶ in which R⁶ has the meaning indicated above,        are reacted    -   with compounds of the general formula (VII)        R⁵-E-X¹  (VII),    -   in which    -   R⁵ and E have the meaning indicated above, and    -   X¹ is a leaving group, preferably mesylate, tosylate or halogen,        particularly preferably bromine or iodine,    -   to give compounds of the general formula (Id)    -   in which    -   R⁵-E-Y- is located at one of positions 2 or 3 of the        thiochromenone ring, and    -   R², R⁵, D, E and Y have the meaning indicated above,    -   in inert solvents which are not changed under the reaction        conditions, and these include halohydrocarbons such as methylene        chloride, trichloromethane or 1,2-dichloroethane, ethers such as        dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other        solvents such as acetone, dimethylformamide, dimethylacetamide,        2-butanone or acetonitrile, preferably tetrahydrofuran,        methylene chloride, acetone, 2-butanone, acetonitrile,        dimethylfornarmide or 1,2-dimethoxyethane, in the presence of a        base such as, for example, alkali metal carbonates such as        cesium carbonate, sodium or potassium carbonate, or sodium or        potassium methanolate, or sodium or potassium ethanolate or        potassium tert-butoxide, or other bases such as sodium hydride,        DBU, preferably potassium tert-butoxidecesium carbonate, DBU,        sodium hydride, potassium carbonate or sodium carbonate, where        appropriate in the presence of potassium iodide, preferably in a        temperature range from room temperature up to refluxing of the        solvents under atmospheric pressure.

The compounds of the general formula (VI) can be prepared from theappropriate precursors for example in analogy to process [M] or by theprocess described for preparing the compounds of the general formula(VIII).

The compounds of the general formula (VII) are known or can be preparedby known processes.

In process

-   [E] compounds of the general formula (VIII)    -   in which    -   hydroxyl is located at one of positions 2 or 3 of the        thiochromenone ring, and    -   R² and D have the meaning indicated above, are reacted    -   with compounds of the general formula (IX)        R¹⁹—X²  (IX),    -   in which    -   R¹⁹ has the meaning indicated above,    -   X² is halogen, preferably bromine,    -   to give compounds of the general formula (Ie)    -   in which    -   R¹⁹—O— is located at one of positions 2 or 3 of the        thiochromenone ring, and    -   R², R¹⁹ and D have the meaning indicated above,    -   in inert solvents which are not changed under the reaction        conditions, and these include solvents such as        dimethylformamide, dimethylacetamide, N-methylpyrrolidone,        pyridine or hexamethylphosphoric triamide, preferably        dimethylformamide, dimethylacetamide, pyridine or        N-methylpyrrolidone, in the presence of a catalyst, preferably        with copper catalysis, Cu(I) catalysts are particularly        preferred, such as, for example, copper(I) iodide, where        appropriate in the presence of a base such as, for example,        alkali metal carbonates such as cesium carbonate, sodium or        potassium carbonate or sodium or potassium methanolate, or        sodium or potassium ethanolate or potassium tert-butoxide, or        other bases such as DBU, pyridine or picoline, with preference        for potassium carbonate or pyridine, preferably in a temperature        range from 80° C. up to the refluxing of the solvents under        atmospheric pressure.

Compounds of the general formula (VIII) are prepared by reactingcompounds of the general formula (If)

-   -   in which    -   methoxy is located at one of positions 2 or 3 of the        thiochromenone ring,    -   and    -   R² and D have the meaning indicated above,    -   with hydrobromic acid in glacial acetic acid, preferably in a        temperature range from 80° C. up to the refluxing of the        solvents under atmospheric pressure.

Compounds of the formula (VIII) can also be prepared by reacting thecompounds of the general formula (If) in an inert solvent, preferablydichloromethane, with boron trichloride or boron tribromide, whereappropriate in the presence of a phase-transfer catalyst, preferablyquaternary ammonium salts, particularly preferably tetrabutylammoniumbromide or iodide, preferably in a temperature range from minus 20° C.up to the refluxing of the solvents under atmospheric pressure.

The compounds of the general formula (If) can be prepared from theappropriate precursors for example in analogy to process [M].

The compounds of the general formula (IX) are kmown or can be preparedby known processes.

In process

-   [F] compounds of the general formula (IX)    -   in which    -   H-T- is located at one of positions 2 or 3 of the thiochromenone        ring,    -   R² and D have the meaning indicated above, and    -   T is O or NR²³ in which R²³ has the meaning indicated for R⁶,    -   are reacted with compounds of the general formula (X)    -   in which    -   R¹ has the meaning indicated above,    -   M is a bond or NR²⁴ in which R²⁴ has the meaning indicated for        R⁶,    -   X³ is halogen, preferably bromine or chlorine,    -   to give compounds of the general formula (Ig)    -   in which    -   R¹-M-SO₂-T- is located at one of positions 2 or 3 of the        thiochromenone ring, and    -   R¹, R², D, M and T have the meaning indicated above,    -   in inert solvents or mixtures of solvents with water, which are        not changed under the reaction conditions, and these include        halohydrocarbons such as methylene chloride, trichloromethane or        1,2-dichloroethane, ethers such as diethyl ether, dioxane,        tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons such as        benzene, xylene or toluene, or other solvents such as acetone,        dimethylformarnide, 2-butanone, acetonitrile or pyridine. It is        likewise possible to employ mixtures of said solvents, where        appropriate also with water. Mixtures with water are, for        example, methylene chloride/water or dioxane/water, with        preference for methylene chloride, methylene chloride/water,        dioxanie, dioxane/water or tetrahydrofuran, where appropriate in        the presence of a phase-transfer catalyst, preferably quatemary        ammonium salts, particularly preferably tetrabutylammonium        chloride or tetrabutylammonium bromide, where appropriate in the        presence of a base such as, for example, alkali metal hydroxides        such as sodium or potassium hydroxide, or alkali metal        carbonates such as cesium carbonate, sodium or potassium        carbonate, or sodium or potassium methanolate, or sodium or        potassium ethanolate or potassium tert-butoxide, or other bases        such as sodium hydride, DBU, triethylamine,        dilsopropylethylamine or pyridine, with preference for pyridine        or sodium hydroxide, preferably in a temperature range from room        temperature up to the refluxing of the solvents under        atmospheric pressure.

The compounds of the general formula (IX) can be prepared in analogy tothe compounds of the general formula (VI).

The compounds of the general formula (X) are known or can be prepared byknown processes.

In process

-   [G] compounds of the general formula (XI)    -   in which    -   R²⁵—NH— is located at one of positinos 2 or 3 of the        thiochromenone ring,    -   R²and D have the meaning indicated above, and    -   R²⁵ has the meaning of R⁶ indicated above,    -   are reacted with compounds of the general formula (XII)        R¹-L-X³  (XI),    -   in which    -   R¹ has the meaning indicated above,    -   X³ has the meaning indicated above,    -   L is CO, SO₂ or NR¹²SO₂ or NR¹⁴CO, in which R¹² and R¹⁴ have the        meaning indicated above,    -   to give compounds of the general formula (Ih)    -   in which    -   R¹-L—NR²⁵— is located at one of positions 2 or 3 of the        thiochromenone ring,    -   and    -   R¹, R², R²⁵, D and L have the meaning indicated above,        -   in inert solvents which are not changed under the reaction            conditions, and these include halohydrocarbons such as            methylene chloride, trichloromethane or 1,2-dichloroethane,            ethers such as diethyl ether, dioxane, tetrahydrofuran or            1,2-dimethoxyethane, or other solvents such as            dimethylformamide, dimethylacetamide, acetonitrile or            pyridine, preferably tetrahydrofuran, pyridine, chloroform            or methylene chloride, in the presence of a base such as,            for example, alkali metal carbonates such as cesium            carbonate, sodium or potassium carbonate, or potassium            tert-butoxide, or other bases such as sodium hydride, DBU,            triethylamine or diusopropylethylamine, preferably            triethylamine, diisopropylethylamine, cesium carbonate,            potassium carbonate, sodium carbonate, pyridine and/or DMAP,            preferably in a temperature range from 0° C. up to the            refluxing of the solvents under atmospheric pressure.

The compounds of the general formula (XI) can be prepared in analogy tothe compounds of the general formula (VI).

The compounds of the general formula (XII) are known or can be preparedby known processes.

In process

-   [H] compounds of the general formula (Ii)    -   in which    -   R¹-L-NH— is located at one of positions 2 or 3 of the        thiochromenone ring,    -   and in which    -   R¹, R², D and L have the meaning indicated above,    -   are reacted with compounds of the general formula (XIII)        R²⁶—X¹  (XIII),    -   in which    -   R²⁶ is (C₃-C₈)-cycloalkyl or optionally unsaturated        (C₁-C₆)-alkyl which is optionally substituted by hydroxyl,        phenyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl or        (C₃-C₈)-cycloalkyl, where phenyl in turn may be substituted by        halogen or (C₁-C₄)-alkyl,    -   X¹ has the meaning indicated above,    -   to give compounds of the general formula (Ij)    -   in which    -   R¹-L—NR²⁶— is located at one of positions 2 or 3 of the        thiochromenone ring, and    -   R¹, R², R²⁶, D and L have the meaning indicated above,        -   in inert solvents which are not changed under the reaction            conditions, and these include halohydrocarbons such as            methylene chloride, trichloromethane, trichloroethane or            1,2-dichloroethane, ethers such as diethyl ether, dioxane,            tetrahydrofuran or 1,2-dirnethoxyethane, or other solvents            such as acetone, dimethylformamide, dimethylacetamide,            N-methylpyrrolidone, 2-butanone or acetonitrile, preferably            tetrahydrofuran, dimethylformamide, 2-butanone or acetone,            in the presence of a base such as, for example, alkali metal            carbonates such as cesium carbonate, sodium or potassium            carbonate, or sodium or potassium methanolate, or sodium or            potassium ethanolate or potassium tert-butoxide, or other            bases such as sodium hydride, DBU, triethylamine or            diisopropylethylarnine, preferably sodium hydride, DBU,            potassium tert-butoxide or potassium carbonate, with, where            appropriate, a phase-transfer catalyst, preferably            tetrabutylammonium bisulfate, preferably in a temperature            range from room temperature to 120° C. under atmospheric            pressure.

The compounds of the general formula (Ij) can be prepared from theappropriate precursors in analogy to process [G].

The compounds of the general formula (XIII) are known or can be preparedby known processes.

In process

-   [I] compounds of the general formula (XIV)    -   in which    -   cyano is located at one of positions 2 or 3 of the        thiochromenone ring, and    -   R² and D have the meaning indicated above,    -   are reacted with an azide, preferably sodium azide, to give        compounds of the general formula (Ik)    -   in which    -   the tetrazole residue is located at one of positions 2 or 3 of        the thiochromenone ring, and    -   R² and D have the meaning indicated above,    -   in inert solvents, preferably toluene or xylene, in the presence        of an acid, preferably triethylammonium hydrochloride,        preferably in a temperature range from 80° C. up to the        refluxing of the solvents under atmospheric pressure.

Where appropriate, compounds of the formula (Ik) are reacted in a secondstep with compounds of the general formula (XV)R²⁷—X³  (XV),

-   -   in which    -   R²⁷ is (C₁-C₆)-alkyl or (C₁-C₆)-acyloxymethyl, and    -   X³ has the meaning indicated above,    -   to give compounds of the general formula (II)    -   in which    -   the heterocycle is located at one of positions 2 or 3 of the        thiochromenone ring, and    -   R², R²⁷ and D have the meaning indicated above,    -   in inert solvents which are not changed under the reaction        conditions, and these include halohydrocarbons such as methylene        chloride, trichloromethane, trichloroethane or        1,2-dichloroethane, ethers such as diethyl ether, dioxane,        tetrahydrofuran or 1,2-dimethoxyethane, or other solvents such        as acetone, dimethylformamide, dimethylacetamide, 2-butanone or        acetonitrile, preferably tetrahydrofuran, methylene chloride,        acetone, 2-butanone or dimethylformamide, in the presence of a        base such as, for example, alkali metal carbonates such as        cesium carbonate, sodium or potassium carbonate, or sodium or        potassium methanolate, or sodium or potassium ethanolate or        potassium tert-butoxide, or other bases such as sodium hydride,        DBU, triethylamine or diisopropylethylamine, preferably sodium        hydride or DBU, preferably in a temperature range from 0° C. up        to the refluxing of the solvents under atmospheric pressure.

Process [I] is also used for appropriate variations of substituents.

Compounds of the general formula (XIV) are prepared for example byreacting compounds of the general formula (II) with Zn(II) cyanide inthe presence of a catalyst in a suitable solvent, and these includeethers such as dioxane, 1,2-dimethoxyethane or diethylene glycoldimethyl ether, or other solvents such as dimethylformamide,dimethylacetamide, N-methylpyrrolidone or acetonitrile, with particularpreference for dimethylformamide or dimethylacetamide, preferably in atemperature range from 60° C. to 160° C. under atmospheric pressure.

The reaction is preferably carried out with catalysis by palladium (D.M. Tschaen, et al., Synth. Commun. 1994, 24, 887; F. Jin, N. P.Confalone, Tetrahedron Lett. 2000, 41, 3271), examples of particularlypreferred catalysts being tetrakis(tri-phenylphosphine)palladium(0) ortris(dibenzylideneacetone)dipalladium in the presence of1,1′-[bis(diphenylphosphino)ferrocene] and zinc.

The compounds of the general formula (XV) are known or can be preparedby known processes.

In process

-   [J] compounds of the general formula (XIV) are reacted in the first    step with hydroxylamine and subsequently with chloroformic esters,    preferably 2-ethylhexyl chloroformate in two further stages to give    compounds of the general formula (Im)    -   in which    -   the heterocycle is located at one of positions 2 or 3of the        thiochromenone ring, and    -   R² and D have the meaning indicated above.

The first reaction step is carried out in inert solvents which are notchanged under the reaction conditions, and these include ethers such asdiethyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane ordiethylene glycol dimethyl ether, hydrocarbons such as benzene, xyleneor toluene, or other solvents such as dimethylformamide,dimethylacetamide, dimethyl sulboxide, pyridine or hexamethylphosphorictriamide, preferably dimethyl sulfoxide, preferably in a temperaturerange from room temperature to 100° C. under atmospheric pressure.

The second reaction step is carried out in inert solvents which are notchanged under the reaction conditions, and these includehalohydrocarbons such as methylene chloride, trichloromethane,1,2-dichloroethane or tiichloroethylene, ethers such as diethyl ether,dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycoldimethyl ether, or other solvents such as dimethylforinamide,dimethylacetainide, 1,2-dimethoxyethane, pyridine orN-methylpyrrolidine, preferably dimethyformamide, where appropriate inthe presence of a base such as, for example, alkali metal carbonatessuch as cesium carbonate, sodium or potassium carbonate, or other basessuch as sodium hydride, DBU, tiiethylamine, diisopropylethylamine orpyridine, preferably pyridine, preferably in a temperature range from 0°C. to room temperature under atmospheric pressure.

The third reaction step is carried out in inert solvents, preferablyxylene, preferably in a temperature range from 10° C. up to therefluxing of the solvents under atmospheric pressure.

Process [J] is also used for appropriate variations of substituents.

In process

-   [K] compounds of the general formula (XV) are reacted first with a    suitable acid to give compounds of the general formula (XVI)    -   in which    -   carboxyl is located at one of positions 2 or 3 of the        thiochromenone ring, and    -   R² and D have the meaning indicated above,    -   preferably in a temperature range from room temperature up to        the refluxing of the solvents under atmospheric pressure.

Acids which are generally suitable are trifluoroacetic acid, sulfuricacid, hydrogen chloride, hydrogen bromide and acetic acid or mixturesthereof, where appropriate with addition of water. Sulfuric acid isparticularly preferably employed.

The compounds of the general formula (XVI) are then reacted withcompounds of the general formula (XVII)

-   -   in which    -   R¹ and R⁹ have the meaning indicated above,    -   to give compounds of the general formula (In)    -   in which    -   R¹R⁹N—CO— is located at one of positions 2 or 3 of the        thiochromenone ring, and    -   R¹, R², R⁹ and D have the meaning indicated above.

Solvents preferred for the reaction with compounds of the generalformula (XVII) are dichloromethane, tetrahydrofuran ordimethylformamide. The reaction takes place in particular at roomtemperature. Aids preferably employed for this reaction are usualcondensing agents such as carbodiimides, e.g. N,N-diethyl-,N,N,′-dipropyl-, N,N′-diisopropyl-, N,N′-dicyclohexylcarbodiimide,N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC),N-cyclohexylcarbodiimide-N′-propyloxymethyl-polystyrene(PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfateor 2-tert-butyl-5-methylisoxazolium perchlorate, or acylaiino compoundssuch as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, orpropanephosphonic anhydride, or isobutyl chloroformate, orbis-(2-oxo-3-oxazolidinyl)phosphoryl chloride orbenzotriazolyloxytri-(dimethylamino)phosphonium hexafluorophosphate, orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), orbenzotriazol-1-yloxytris(dimethylammno)phosphonium hexafluorophosphate(BOP). Bases employed are alkali metal carbonates, e.g. sodium orpotassium carbonate or bicarbonate, or organic bases such astrialkylamines, e.g. triethylamine, N-methylmorpholine,N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylarnine.Particular preference is given to the combination ofN-cyclohexylcarbodiimide-N′-propyloxym ethyl-polystyrene(PS-carbodiimide) and 1-hydroxybenzotriazole (HOBt) and to thecombination of benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (BOP) and triethylamine.

The compounds of the general formula (XVII) are known or can be preparedby known processes.

In process

-   [L] compounds of the general formula (XI) are reacted with compounds    of the general formula (XVIII)    -   in which    -   R¹ has the meaning indicated above,    -   to give compounds of the general formula (Io)    -   in which    -   R¹—NH—CO—NR¹⁵— is located at one of positions 2 or 3 of the        thiochromenone ring, and    -   R¹, R², R¹⁵ and D have the meaning indicated above,    -   in inert solvents which are not changed under the reaction        conditions, and these include halohydrocarbons such as methylene        chloride, trichloromethane or 1,2-dichlorethane, ethers such as        diethyl ether, dioxane, tetrahydrofuran or glycol dimethyl        ether, hydrocarbons such as benzene, xylene or toluene, or other        solvents such as acetone, dimethylforrnamide, dimethylacetamide,        2-butanone, acetonitrile or pyridine, preferably        tetrahydrofuran, pyridine or methylene chloride, where        appropriate in the presence of a base such as alkali metal        carbonates such as cesium carbonate, sodium or potassium        carbonate, or potassium tert-butoxide, or other bases such as        sodium hydride, DBU, triethylamine, pyridine or        diisopropylethylamine, preferably triethylamine, pyridine or        diisopropylethylarmine, preferably in a temperature range from        room temperature up to the refluxing of the solvents under        atmospheric pressure.

The compounds of the general formula (XVIII) are known or can beprepared by known processes.

In process

-   [M] compounds of the general formula (XIX)    -   in which    -   R²⁸ is (C₁-C₆)-alkyl or benzyl, preferably ethyl or methyl,    -   and    -   D has the meaning indicated above,    -   are reacted with compounds of the general formula (XX)    -   in which    -   R¹, R² and A have the meaning indicated above,    -   in polyphosphoric acid to give compounds of the general formula        (I)    -   in which    -   R¹-A- is located at one of positions 2 or 3 of the        thiochromenone ring, and    -   R¹, R², A and D have the meaning indicated above,    -   preferably in a temperature range from 70° C. to 110° C. under        atmospheric pressure.

Compounds of the formula (XX) which are preferably employed are thosewhich are stable under the reaction conditions used.

The cyclic keto esters (XIX) are known or can be prepared by generallyknown processes, e.g. by Claisen condensation of the cyclic ketones withdialkyl carboxylates (e.g. S. J. Rhoads et al., Tetrahedron 1963, 19,1625), or with dialkyl oxalates followed by decarboxylation (e.g. L. Re,H. Schinz, Helv. Chim. Acta 1958, 41, 1695).

The cyclic ketones are known or can be prepared by generally knownprocesses, e.g. from the corresponding cyclo-2-alkenones or1,3-diketones.

The compounds and (XX) are known or can be prepared by known methods.Dimercaptobenzenes substituted on one sulfur can be prepared for exampleby the method of J. Campbell et al. J. Org. Chem. 1964, 29, 1830-1833;Rumpf et al., Bull. Soc. Chim. Fr. 1940, 7, 632. 3-Sulfonylthiophenolscan be prepared for example by the method of Melloni et al., J. Chem.Soc., Perkin Trans. 1972, 1, 218; Borwell et al. 1953, 75, 6019.3-Mercaptobenzenesulfonic acids can be prepared by the method of H.Kawai et al., Chem. Pharm. Bull. 1991, 39, 1422-1425.

In process

-   [N] compounds of the general formula (Ip)    -   in which    -   R² and D have the meaning indicated above,    -   are reacted with compounds of the general formula (XXI)    -   in which    -   R¹ has the meaning indicated above,    -   to give compounds of the general formula (Iq)    -   in which    -   R¹CO— is located at one of positions 2 or 3 of the        thiochromenone ring, and    -   R¹, R² and D have the meaning indicated above,    -   in inert solvents which are not changed under the reaction        conditions, and these include halohydrocarbons such as        tetrachloroethane, 1,2-dichloroethane or chlorobenzene, or other        solvents such as dimethylformamide, preferably        dimethylformamide, preferably in the presence of aluminum        trichloride, preferably under Friedel-Crafts acylation        conditions analogous to the conditions described in the        literature (O. Diouf et al., Eur. J. Med. Chem. 1995, 30,        715-719; S. Yous et al., J. Org. Chem. 1994, 59, 1574-1576).

The corresponding methyl ketones [R¹ is methyl in (Ip)] can additionallybe obtained from the compounds of the general formula (II) preferably bymeans of a Heck or Stille reaction by methods known from the literature(W. Cabri et al., Tetrahedr. Lett. 1991, 32, 1753-1756; M. Kosugi etal., Bull. Chem. Soc. Jpn. 1987, 60, 767-768.). The methyl ketones can,where appropriate, be further derivatized after bromination of themethyl group under standard conditions usual for this purpose.

The compounds of the general formula (Ip) can be prepared from theappropriate precursors for example in analogy to process [M].

The compounds of the general formula (XXIII) are known or can beprepared by known processes.

In process

-   [O] compounds of the general formula (Ir)    -   in which    -   R¹—S— is located at one of positions 2 or 3 of the        thiochromenone ring, and    -   R¹, R² and D have the meanings indicated above,    -   are reacted with oxidizing agents such as, for example,        m-chloroperbenzoic acid, to give compounds of the general        formula (Is)    -   in which    -   R¹—SO— is located at one of positions 2 or 3 of the        thiochromenone ring, and    -   R¹, R² and D have the meaning indicated above,        -   for example under the conditions described in the literature            (P. Margaretha et al., Helv. Chim. Acta 1979, 62,            1978-1979; P. Bendazzoli et al., Tetrahedr. Lett. 1993, 34,            2975-2978.).

The compounds of the general formula (Ir) can be prepared from theappropriate precursors for example in analogy to process [M].

In process

-   [P] compounds of the general formula (XXII)    -   in which    -   nitro is located at one of positions 2 or 3 of the        thiochromenone ring, and    -   R² and D have the meaning indicated above,    -   are reacted with the appropriate sulfinic acid salts to give        compounds of the general formula (It)    -   in which    -   R¹—SO₂— is located at one of positions 2 or 3 of the        thiochromenone ring, and    -   R¹, R² and D have the meaning indicated above,    -   preferably under the conditions described in the literature (W.        Fischer et al., Helv. Chim. Acta 1985, 68, 854-59.).

The compounds of the general formula (XXII) can be prepared from theappropriate precursors for example in analogy to process [M].

In process

-   [Q] compounds of the general formula (Iu)    -   in which    -   amino is located at one of positions 2 or 3 of the        thiochromenone ring, and    -   R² and D have the meaning indicated above,    -   are converted after azotization into the corresponding sulfonic        acids, and the latter are subsequently reacted with compounds of        the general formula (XXIII)        R¹—U—H  (XXIII),    -   in which    -   R¹ has the meaning indicated above, and    -   U is O or NR¹⁰ in which R¹⁰ has the meaning indicated above,    -   to give compounds of the general formula (Iv)    -   in which    -   R¹—U—SO₂— is located at one of positions 2 or 3 of the        thiochromenone ring, and    -   R¹, R², D and U have the meaning indicated above.

The first reaction step is preferably carried out under the conditionsdescribed in the literature (Meerwein et al., Chem. Ber. 1957, 90,841-51; Polak et al., Recl. Trav. Chim. Pays-Bas 1910, 29, 423.).

In the second stage, the sulfonic acids can be converted, whereappropriate via their chlorides, by esterification or amination bymethods known to the skilled worker into the corresponding sulfonates orsulfonamides.

The compounds of the general formula (It) are prepared as described forcompounds of the general formula (XI).

The compounds of the general formula (XXIII) are known or can beprepared by known processes.

Amines in side chains can also be prepared by reductive amination ofcorresponding aldehydes with appropriate amines. Examples which may bementioned are:

The processes described above can be illustrated by way of example bythe following formula diagrams:

The compounds of the invention of the general formula (I) are suitablefor use as medicaments in the treatment of humans and animals.

The compounds of the invention show a valuable range of pharmacologicaleffects which could not have been predicted.

They are distingished as mGluR1 receptor antagonists.

The compounds of the invention can, by reason of their pharmacologicalproperties, be employed alone or in combination with other medicamentsfor the treatment and/or prevention of neuronal damage or disordersconnected with derangement of the physiological or pathophysiologicalstates of the glutamatergic system in the central and peripheral nervoussystem.

For the treatment and/or prevention of neuronal damage, for example, byischemic, thromb- and/or thromboembolic, and haemorrhagic stroke,conditions following direct and indirect injuries in the region of thebrain and of the skull. Also for the treatment and/or prevention ofcerebral ischemias after all surgical procedures on the brain orperipheral organs or body parts and associated or preceding conditionsof a pathological or allergic nature which may lead primarily and/orsecondarily to neuronal damage.

The compounds of the invention are likewise also suitable for thetherapy of primary and/or secondary pathological conditions of thebrain, for example during or after cerebral vasospasms, hypoxia and/oranoxia of an origin not previously mentioned, perinatal asphyxia,autoimmune diseases, metabolic and organic disorders which may beassociated with damage to the brain, and damage to the brain as a resultof primary brain disorders, for example epilepsy and atheroscleroticand/or arteriosclerotic changes. For the treatment of chronic orpsychiatric disorders such as, for example, depression,neurodegenerative disorders such as, for example, Alzheimer's,Parkinson's or Huntington's disease, multiple sclerosis, amyotrophiclateral sclerosis, neurodegeneration owing to acute and/or chronic viralor bacterial infections and multi-infarct dementia.

They can moreover be employed as medicaments for the treatment ofdementias of varying origins, cognitive impairments in the elderly,memory impairments, spinal cord injuries, states of pain, anxiety statesof varying origins, drug-related Parkinson's syndrome, psychoses (suchas, for example, schizophrenia), cerebral edema, neuronal damagefollowing hypoglycemia, emesis, nausea, obesity, addictive disorders andwithdrawal symptoms, CNS-mediated convulsions, sedation and movementdisorders.

The compounds of the invention of the general formula (I) canadditionally be used to promote neuronal regeneration in the post-acutephase of cerebral injuries or chronic disorders of the nervous system.

The compounds of the invention can be employed alone or in combinationwith other medicaments for the prophylaxis and treatment of acute and/orchronic pain (for a classification, see “Classification of Chronic Pain,Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms”,2nd edition, Meskey and Begduk, Editors; IASP-Press, Seattle, 1994) andneurodegenerative disorders, especially for the treatment ofcancer-induced pain and chronic neuropathic pain like, for example, thatassociated with diabetic neuropathy, post-herpetic neuralgia, peripheralnerve damage, central pain (for example the consequence of cerebralischemia) and trigeminal neuralgia, and other chronic pain such as, forexample, lumbago, backache (low back pain) or rheumatic pain. Thesesubstances are in addition also suitable for the therapy of primaryacute pain of any origin and of secondary states of pain resultingtherefrom, and for the therapy of states of pain which were formallyacute and have become chronic.

They are preferably employed as medicaments for the treatment and/orprophylaxis of states of pain and neurodegenerative disorders.

Modulation of substances at the metabotropic glutamate receptor (director indirect influencing of the efficiency of coupling of the glutamatereceptor to the G proteins) can be examined on primary cultures ofgranule cells from the cerebrum. Electrophysiological measurements onthese cell cultures in the cell attached mode show that L-type Ca²⁺channels in this preparation are activated by mGluR1 glutamate receptors(J. Neurosci. 1995, 15, 135), whereas they are blocked by group IIreceptors J. Neurosci. 1994, 14, 7067-7076). The modulating effect ofpharmacological test substances on glutamate receptors can be checked byan appropriate experimental arrangement. A detailed examination of thesubtype specificity under controlled conditions is possible on Xenopusoocytes through injection of the appropriate mGluR subtype DNA (WO92/10583).

The in vitro effect of the compounds of the invention on mGluR1receptors can be shown by the following biological assays:

1. Determination of the activity on the mGluR1 receptor

mGluR1 receptor-expressing CHO cells are seeded in 96-well plates(Greiner, Frickenhausen, Germany) (20 000 cells/well) and cultivated inultra CHO medium (Bio-Whittaker, Walkersville, Md., 10% fetal calfserum) for one day. The substances to be tested are initially dissolvedin a concentration of 10⁻² M in 100% DMSO and then diluted to thedesired concentration with the culture medium. After being washed oncewith cell culture medium, the cells are incubated with 1 mM glutamateand simultaneously with the substance to be tested at 37° C. for 4 h.The medium is then aspirated off and the cells are lysed with 75 μl ofTriton-luciferase buffer (1% Triton X 100, 10% glycerol, 2 mM DTT, 25 mMNa2HPO4, 25 mM TRIS), (530 μM ATP, 470 μM luciferin, 270 μM CoA, 20 mMtricine, 2.67 mM MgSO4, 33.3 mM DTT, 0.1 mM EDTA, pH 7.8). Theluminescence is measured after one minute using a camera (Hamamatsu,Japan). Cells incubated only with glutamate show a marked increase inthe luminescence compared with controls, while mGluR1 receptorantagonists reduce this concentration-dependently to below the initialluminscence.

The following examples showed the following effect in the abovementionedassay: TABLE 1 Example IC₅₀ [nM] 1-3  9 1-10 97 1-27 23 1-29 21 1-31 311-34 81 3-21 22 3-22 13 3-23 28 3-49 35 3-55 35 4-08 25

The suitability of the compounds of the invention for the treatment ofstates of pain, especially states of neuropathic pain, can be shown inthe following animal models:

2. Axotomy of sciatic branches in the rat (chronic pain model)

Under pentobarbital anesthesia, the trifurcation of a sciatic nerve isexposed, and the peroneal and tibial branches are axotomized after thenerves have been ligated proximal of the axotomy site. Control animalsundergo a sham operation. After the operation, the axotomized animalsdevelop chronic mechanical allodynia and thermal hyperalgesia.

The mechanical allodynia is tested, comparing with sham-operatedanimals, with the aid of a pressure transducer (electronic von Freyanesthesiometer, ITC Inc.-Life Science Instruments, Woodland Hills,Calif., USA).

The thermal hyperalgesia can be detemirned by measuring the latency timewithin which a rat removes a paw from the area of a radiant heat source(plantar test, Ugo Basile (Milan)).

The substance is administered by various administration routes (i.v.,i.p., orally, i.t., i.c.v., transdermally) at various times before thepain testing.

3. Ligature of the sciatic nerve in the rat according to Bennett andXie, 1988 (chronic pain model)

Bennett und Xie: A peripheral mononeuropathy in the rat that producesdisorders of pain sensation like those seen in man. Pain 1988, 33,87-107.

Under pentobarbital anesthesia, the sciatic nerve is exposedunilaterally and ligated (4 ligatures approximately 1 mm apart, proximalto the trifurcation of the nerve). Control animals undergo a shamoperation. After the operation, the ligated animals develop a chronicmechanical and thermal hyperalgesia. The hyperalgesia is tested,comparing with sham-operated animals, with the aid of a pressuretransducer (mechanical hyperalgesia; electronic von Freyanesthesiometer, IITC Inc.-Life Science Instruments, Woodland Hills,Calif., USA) or an infrared source (thermal hyperalgesia; Plantar Test,Hugo Basile Inc., Comerio, Italy).

The substance is administered by various administration routes (i.v.,i.p., orally, i.t., i.c.v., transdermally) at various times before thepain testing.

The suitability of the compounds of the invention for the treatment ofstates of pain, especially inflammation-related states of pain, can beshown in the following animal model.

4. Model of acute inflammatory pain (carrageenin model) in rats.

This method, which tests analgesic effect in rats suffering frominflammatory pain, follows the description of Winter et al. (Proc. Soc.Exp. Biol. Med., 1962, 111, 544-547.

Rats receive subplantar injection into the right rear paw of asuspension of carrageenin (0.75 mg per paw in 0.05 ml of physiologicalsaline). Two hours later, the rats undergo successive thermal andtactile stimulation both on the noninflamed and on the inflamed rearpaw.

The apparatus for thermal stimulation (Ugo Basile, Ref.: 7371) consistsof 6 individual Plexiglas boxes (17×11×13 cm) placed on an elevatedglass plate. A rat is placed in the box for 10 min for habituation. Amovable infrared source (setting 20) is then focused under thenoninflamed and the inflamed rear paw, and the latency time until thepaw is withdrawn are recorded automatically. The withdrawal of the pawinterrupts the reflected beam and thus automatically switches off thecounter and light source. To avoid tissue damage, the test is stoppedafter 45 s even if no paw-withdrawal is recorded.

For the tactile stimulation, the animal is placed in a Plexiglas box(17×11×13 cm) whose base consists of a wire mesh. The tip of anelectronic Von-Frey filament (Bioseb, Model 1610) is pushed withincreasing pressure against the uninflamed and the inflamed rear paw,and the force required to bring about withdrawal of the paw isautomatically recorded.

The testing is carried out three times and the average force per paw iscalculated as the result for each animal.

12 rats are investigated per group: male Wistar (Han) rats, 180-220 g.The test is carried out blind.

Morphine (8 mg/kg i.p.) and acetylsalicylic acid (256 mg/kg i.p.),administered under the same experimental conditions, serve as referencesubstances.

Data analysis takes place by comparing the treated groups with thecorresponding controls by means of the unpaired Student's test.

The novel active substances can be converted iin a known manner intoconventional formulations such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, nontoxic, pharmaceutically suitable carriers or solvents. Inthese, the therapeutically active compound should be present in eachcase in a concentration of about 0.5 to 90% by weight of the completemixture, i.e. in amounts which are sufficient to achieve the stated doserange.

The formulations are produced for example by extending the activesubstances with solvents and/or carriers, where appropriate with use ofemulsifiers and/or dispersants, it being possible, for example whenwater is used as diluent, where appropriate to use organic solvents asauxiliary solvents.

Administration takes place in a conventional way, preferably orally,transdermally or parenterally, especially perlingually or intravenously.However, it can also take place by inhalation through the mouth or nose,for example with the aid of a spray, or topically via the skin.

It has generally proved advantageous to administer amounts of about0.001 to 10 mg/kg, on oral administration preferably about 0.005 to 3mg/kg, of body weight to achieve effective results.

It may nevertheless be necessary where appropriate to deviate from theamounts mentioned, in particular as a function of the body weight andthe mode of administration, on the individual response to themedicament, the nature of its formulation and the time or interval overwhich administration takes place. Thus, in some cases it may besufficient to make do with less than the aforementioned minimum amount,whereas in other cases the upper limit mentioned must be exceeded. Wherelarger amounts are administered, it may be advisable to distribute thesein a plurality of single doses over the day.

Abbreviations

-   abs. absolute-   Ac acetyl-   acac acetylacetonyl-   AIBN α,α-azobis(isobutyronitrile)-   Aloc allyloxycarbonyl-   aqueous aqueous-   aq. aqueous-   9-BBN 9-borabicyclo[3.3.1]nonane-   Bn benzyl-   Boc tert-butoxycarbonyl-   Bom benzyloxymethyl-   BOP benzotriazol-1-yloxy-tris(dimethylamino)phosphonium    hexafluorophosphate-   b.p. boiling point-   Bu butyl-   Bz benzoyl-   CAN cerium ammonium nitrate-   Cbz benzyloxycarbonyl-   CDI N,N′-carbonyldiimidazole-   cf. compare-   CH cyclohexane-   conc. concentrated-   Cp cyclopentadienyl-   cryst. crystalline/crystallized-   CSA 10-camphorsulfonic acid-   Dabco 1,4-diazabicyclo[2.2.2]octane-   DAST diethylaminosulfur trifluoride-   DBN -1,5-diazabicyclo[4.3.0]non-5-ene-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   DCC N,N′-dicyclohexylcarbodiimide-   DCE 1,2-dichloroethane-   DCI direct chemical ionization (in MS)-   DCM dichloromethane-   DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone-   DEAD diethyl azodicarboxylate-   d.e. diastereomeric excess-   decomp. decomposition-   dil. diluted-   DHP 3,4-dihydro-2h-pyran-   DIAD diisopropyl azodicarboxylate-   DIBAH diisobutylalurninum hydride-   DIC diisopropylcarbodiimide-   DEEA N,N-diisopropylethylamine-   dist. distilled-   DMA N,N-dimethylacetamide-   DMAP 4-N,N-dimethylaminopyridine-   DME 1,2-dimethoxyethane-   DME N,N-dimethylformamide-   DMPU N,N′-dimethylpropylene urea-   DMSO dimethyl sulfoxide-   DNPH 2,4-dinitrophenylhydrazine-   DPPA diphenylphosphoryl azide-   EA ethyl acetate-   EDC N′-(3-dimethylaminopropyl)-n-ethylcarbodiimide x hc1-   e.e. enantiomeric excess-   EI electron impact ionization (in ms)-   eq equivalent(s)-   ESI electrospray ionization (in ms)-   Et ethyl-   Fmoc fluorenylmethoxycarbonyl-   Fr. fraction-   GC gas chromatography-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HMDS 1,1,1,3,3,3-hexamethyldisilazane-   HMPA or HMPT hexamethylphosphoric triamide-   HOBt -hydroxy-1h-benzotriazole x h₂o-   HOSu N-hydroxysuccinimide-   HPLC high pressure, high performance liquid chromatography-   Im irnidazol-1-yl-   IR infrared spectroscopy-   LAH lithium aluminum hydride-   LC-MS coupled liquid chromatography—mass spectroscopy-   LDA lithium-N,N-diisopropylamide-   LiHMDS lithium-N,N-bistrimethylsilylamide-   liq. liquid-   Lit. literature (reference)-   m meta-   mCPBA meta-chloroperbenzoic acid-   Me methyl-   MEK methyl ethyl ketone-   MEM methoxyethoxymethyl-   MOM methoxymethyl-   m.p. melting point-   MPLC medium pressure liquid chromatography-   Ms methanesulfonyl (Mesyl)-   MS mass spectroscopy-   MTBE methyl tert-butyl ether-   MW molecular weight-   NBS N-bromosucciniride-   NCS N-chlorosuccinimide-   NIS N-iodosuccinimide-   NMM N-methylmorpholine-   NMO N-methylmorpholine n-oxide-   NMR nuclear magnetic resonance spectroscopy-   o ortho-   p para-   p.A. analytical grade-   PCC pyridinium chlorochromate-   PDC pyridinium dichromate-   Pfp pentafluorophenyl-   Ph phenyl-   Piv pivaloyl-   PMB p-methoxybenzyl-   PNB p-nitrobenzyl-   PPA polyphosphoric acid-   PPTS pyridinium p-toluene sulfonate-   Pr propyl-   prec. precipitate-   PS polystyrene (resin)-   py pyridine-   PyBOP benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium    hexafluorophosphate-   RF reflux-   R_(f) retention index (in TLC)-   RP reverse phase (in HPLC)-   RT room temperature-   R_(t) retention time (in HPLC)-   sat. saturated-   SEM ²-(trimethylsilyl)ethoxymethyl-   sol. solution-   subl. sublime-   TBAF tetrabutylammonium fluoride-   TBAI tetrabutylammonium iodide-   TBDMS tert-butyldimethylsilyl-   TBDPS tert-butyldiphenylsilyl-   TBTU o-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   TEA triethylamine-   techn. technical-   Teoc 2-(trimethylsilyl)ethoxycarbonyl-   TES triethylsilyl-   Tf trifluoromethanesulfonyl-   TFA trifluoroacetic acid-   TFAA trifluoroacetic anhydride-   TfOH trifluoromethanesulfonic acid-   THF tetrahydrofuran-   THP tetrahydropyranyl-   TIPS triisopropylsilyl-   titr. titrated-   TLC thin layer chromatography-   TMEDA N,N,N′N′-tetramethylethylenediamine-   TMOF trimethyl orthoforrnate-   TMS trimethylsilyl-   TPP triphenylphosphine-   TPPO triphenylphosphine oxide-   Trt trityl-   Ts p-toluenesulfonyl (Tosyl)-   TsOH p-toluenesulfonic acid-   v/v volume to volume ratio (of a solution)-   Vol. volume-   w/w weight to weight ratio (of a solution)-   Z benzyloxycarbonyl

STARTING COMPOUNDS I

The retention time of starting compounds and preparation examples wasdetermined by HPLC under the following conditions.

HPLC Method:

Column: Chromasil C18 60*2; volume injected 1.00 μl; flow rate: 0.75ml/min; eluent: A=5 ml HClO₄/l H₂O, B=CH₃CN; gradient [t(min): A/B]:0.5: 98/2; 4.5: 10/90; 6.5: 10/90; 6.7: 98/2; 7.5: 98:2.

Preparative HPLC method: Reverse phase, ACN/water gradient; column:GROM-SIL 120 ODS-4 HE 10 μm, 250* 30 mm

EXAMPLE I-1 6-Bromo-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

The reaction is carried out in an apparatus with mechanical stirrerunder argon, and off-gases are passed through chlorine bleach solution.

110 g of polyphosphoric acid are introduced under a strong argon streamand stirred at RT for 15 min under a strong argon stream, and thereaction flask is then heated with a hot-air blower for about 5 minuntil a lower viscosity is evident. It is allowed to cool again, 10.0 g(51.3 mmol) of 3-bromothiophenol and 11.2 g (56.4 mmol) of ethyl4-ethyl-2-oxocyclohexylcarboxylate are added with disposable syringes,and the mixture is stirred at normal temperature for some minutes. Thehoney-like reaction mixture changes color to beige and is heated to 90°C. and then stirred at this temperature for 2 h.

For working up, the mixture is allowed to cool to normal temperature,and firstly about 300 g of ice and 50 ml of water are added and, after10 min, 300 ml of dichloromethane are also added, and the mixture isstirred at normal temperature for 20 min. After phase separation, theaqueous phase is extracted with dichloromethane (3×330 ml). The organicphases are washed twice with 200 ml of 1N sodium hydroxide solution eachtime and once with 100 ml of saturated brine, dried over magnesiumsulfate and concentrated in a rotary evaporator.

The 17.8 g of crude product obtained in this way are recrystallizedseveral times from about 150 ml of petroleum ether p.A. (60°-80°) eachtime to move the 8-bromo regioisomer.

5.55 g (34%) of the target compound are obtained in this way.

MS (EI+): 322 (M);

¹H-NMR (400 MHz, CDCl₃): δ=0.99 (t, J=7.5 Hz; 3H); 1.33-1.46 (m, 3H);1.66-1.76 (m, 1H); 2.01-2.07 (m, 1H); 2.37-2.55 (m, 2H); 2.68-2.73 (m,1H); 2.88-2.93 (m, 1H); 7.55-7.57 (dd, J=8.5 Hz, 2 Hz; 1H); 7.66 (d, J=2Hz, 1H); 8.34 (d, J=8.5 Hz; 1H).

The following were prepared in analogy to the method of Example I-1:

EXAMPLE I-23-Bromo-6,7,8,9,10,11-hexahydro-12H-cycloocta[b]thiochromen-12-one

MS (EI+): 322 (M);

¹H-NMR (200 MHz, DMSO): δ=1.29-1.63 (m, 6H); 1.70-1.83 (m, 2H);2.82-2.90 (m, 4H); 7.71-7.76 (dd, J=8.5 Hz, 2 Hz, 1H); 8.17 (d, J=2 Hz;1H); 8.19-8.24 (d, J=8.5 Hz; 1H).

EXAMPLE I-36-Bromo-3,3-dimnethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (EI+): 322 (M);

¹H-NMR (300 MHz, CDCl₃): δ=1.03 (s, 6H); 1.62 (t, J=6.5 Hz; 2H); 2.46(s, 2H); 2.70 (m, 2H); 7.55-7.58 (dd, J=8.5, 2 Hz; 1H); 7.67 (d, J=2 Hz;1H); 8.35 (d, J=8.5 Hz; 1H).

EXAMPLE I-4 6-Bromo-3-spirobutyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (EI+): 334 (M);

¹H-NMR (300 MHz, CDCl₃): δ=1.82-1.96 (m, 8H); 2.67-2.73 (m, 4H);7.53-7.59 (dd, J=8.5, 2 Hz; 1H); 7.67 (d, J=2 Hz; 1H); 8.33 (d, J=8.5Hz; 1H).

EXAMPLE I-53-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carbonitrile

2.00 g (5.02 mmol) of6-bromo-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one (Example I-1),0.62 g (5.27 mmol) of zinc cyanide and 0.58 g (0.50 mmol) oftetra-kis(triphenylphosphine)palladium(0) are dissolved in 20 ml of DMFunder argon and heated at 80° C. overnight.

For working up, cooling to normal temperature is followed by 15 ml of25% strength ammonia solution and 25 ml of water being added, and theprecipitate being filtered off and washed with 75 ml of water. Drying invacuo and recrystallization from cyclohexane/ethyl acetate (3:2) affords1.28 g (95%) of the target compound.

MS (CI+): 287 (M+NH₄), 270 (M+H);

¹H-NMR (200 MHz, DMSO): δ=0.94 (t, J=7 Hz; 3H); 1.24-1.46 (m, 3H);1.57-1.77 (m, 1H); 1.89-2.04 (m, 1H); 2.30-2.56 (m, 2H); 2.67-2.85 (m,2H); 7.91-7.9 (dd, J=8.5 Hz, 1.5 Hz; 1H); 8.38-8.42 (d, J=8.5 Hz; 1H);8.49 (d, J=1 Hz; 1H).

EXAMPLE I-6 3-Ethyl-6-hydroxy-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

1.00 g (3.64 mmol) of3-ethyl-6-methoxy-1,2,3,4-tetrahydro-9H-thioxanthen-9-one (Example 1-1)is introduced in 20 ml of acetic acid and, after addition of 8 ml of 48%strength hydrobromic acid, the mixture is stirred overnight and for afurther three days at the reflux temperature until the precursor hascompletely reacted.

Working up is by substantially concentrating in a rotary evaporator,adding the residue to water and extracting the mixture three times withethyl acetate. The combined organic phases are dried and concentrated.The crude product obtained in this way is absorbed onto silica gel andflash-chromatographed on about 150 g of silica gel, starting withcyclohexane and then with a cyclohexane/ethyl acetate 20:1 to 5:1gradient. The product fractions are recrystallized fromcyclohexane/ethyl acetate 5:1.

655 mg (69%) of the target compound are obtained in this way.

MS (CI+): 261 (M+H);

¹H-NMR (300 MHz, DMSO): δ=0.93 (t, J=7.5 Hz; 3H); 1.25-1.41 (m, 3H);1.56-1.68 (m, 1H); 1.88-1.96 (m, 1H); 2.26-2.43 (m, 2H); 2.62-2.75 (m,2H); 6.95 (m, 2H); 7.05-7.32 (m, b, 1H); 8.16-8.19 (m, 1H).

EXAMPLE I-73-Ethyl-N′-hydroxy-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carboximidamide

129 mg (1.86 mmol) of hydroxylammonium chloride are introduced into 1 mlof DMSO under argon, 0.26 ml (1.86 mmol) of triethylamine is added, andthe mixture is stirred for about 5 min. The insoluble solid is filteredoff and washed with tetrahydrofuran. The filtrate is freed of THF in arotary evaporator and, after dropwise addition of 100 mg (0.37 mmol) of3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carbonitrile (ExampleI-5) dissolved in DMSO to the remaining DMSO solution, the reactionmixture is stirred at 75° C. overnight.

For working up, the reaction mixture is diluted with 3 ml of DMSO/2 mlof acetonitrile and purified without further treatment by preparativeHPLC. 85.3 mg (76%) of the target compound are obtained in this way.

MS (EI+): 302 (M);

¹H-NMR (200 MHz, DMSO): δ=0.95 (t, J=7 Hz; 3H); 1.24-1.46 (m, 3H);1.56-1.76 (m, 1H); 1.88-2.03 (m, 1H); 2.28-2.43 (m, 2H); 2.71 (m, 1H);2.80 (m, 1H); 6.04 (s, 2H); 7.84-7.89 (dd, J=8.5 Hz, 1.5 Hz, 1H); 7.99(s, 1H); 8.26 (d, J=8.5 Hz; 1H); 10.03 (s, 1H).

The following were prepared in analogy to the method of Example I-7:

EXAMPLE I-8N′-Hydroxy-12-oxo-6,8,9,10,11,12-hexahydro-7H-cycloocta[b]thiochromene-3-carboximidamide

MS (EI+): 302 (M);

¹H-NMR (200 MHz, DMSO): δ=1.32-1.50 (m, 4H); 1.54-1.63 (m, 2H);1.73-1.82 (m, 2H); 2.85-2.91 (m, 4H); 6.04 (s, 2H); 7.86-7.89 (dd, J=8.5Hz, 1.5 Hz, 1H); 8.02 (d, J=1.5 Hz; 1H); 8.29 (d, J=8.5 Hz; 1H); 10.32(s, 1H).

EXAMPLE I-9N′-Hydroxy-3,3-dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carboximidamide

MS (CI+): 303 (M+H);

¹H-NMR (300 MHz, DMSO): δ=0.99 (s, 6H); 1.58 (t, J=6.5 Hz; 2H);2.53-2.59 (m, 4H); 6.03 (s, 2H); 7.85-7.89 (dd, J=8.5 Hz, 1.5 Hz, 1H);8.00 (d, J=1.5 Hz; 1H); 8.28 (d, J=8.5Hz; 1H); 10.03 (s, 1H).

EXAMPLE I-106-Chloro-3-ethyl-7-fluoro-6-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

60 g of polyphosphoric acid are heated at 110° C. under argon for 10min. After cooling, 5.00 g (29.8 mmol) of 3-chloro-4-fluorophenylthioland 6.50 g (32.8 mmol) of ethyl 4-ethyl-2-oxo-cyclohexanecarboxylate areadded, and the mixture is stirred at an oil bath temperature of 90° C.for 3.5 h. 200 g of ice and 200 ml of dichloromethane are added to thereaction mixture and, after thawing, the phases are separated. Theaqueous phase is extracted twice more with dichloromethane, and thecombined organic phases are washed twice with sodium hydroxide solution(1 N) and once with saturated aqueous sodium chloride solution. Afterdrying over sodium sulfate and filtration, the solvent is removed bydistillation under weak vacuum. The major part of the pure product isobtained by stirring the resulting solid in cyclohexane. Chromatographyof the filtrate on silica gel (0.04-0.063 nm) with cyclohexane/ethylacetate 40:1/30:1/20:1/10:1 as mobile phase affords a mixture which issubsequently purified by preparative HPLC.

Yield: 3.114 g (35.2% of theory).

R_(f) (cyclohexane/ethyl acetate 5:1)=0.65.

MS (EI): 297 (M+H).

HPLC, retention time=5.69 min (LC-MS).

¹H-NMR (200 MHz, CDCl₃): δ=0.99 (t, 3H), 1.32-1.51 (m, 3H), 1.59-1.82(m, 1H), 1.97-2.13 (m, 1H), 2.32-2.60 (m, 2H), 2.62-2.80 (m, 1H),2.81-2.99 (m, 1H), 7.58 (d, 1H), 8.24 (d, 1H).

EXAMPLE I-113-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carboxylic acid

0.281 g (1.05 mmol) of3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carbonitrile (ExampleI-5) is stirred in 5.5 ml of sulfuric acid (70% in water) at 120° C. for2.5 h. After cooling, the solution is added to 2 ml of ice-water, andthe resulting precipitate is initially filtered off and then taken up insodium bicarbonate (10% strength aqueous solution). The carboxylic acidprecipitates as a white solid after acidification with sulfuric acid(70% in water).

Yield: 262.8 mg (87.2% of theory).

R_(f) (CHCl₃:MeOH:AcOH:H₂O=120:30:3:3)=0.85.

MS (EI): 288 (M).

HPLC, retention time=4.64 min.

¹H-NMR (200 MHz, CDCl₃): δ=0.82 (t, 3H), 1.14-1.35 (m, 3H), 1.43-1.65(m, 1 H), 1.78-1.95 (m, 1H), 2.18-2.44 (m, 2H), 2.50-2.81 (m, 2H), 7.87(dd, 1H), 8.05 (d, 1H), 8.32 (d, 1H), 12.63 (br. s, 1H).

EXAMPLE I-12 Ethyl (4,4-diethyl-2-oxocyclohexyl)carboxylate

634 mg (4.62 mmol) of phosphorus trichloride are added dropwise to 2.1 g(12.5 mmol) of 5,5-diethylcyclohexane-1,3-dione (Kon, G. .A. R.,Linstaed, R. P., J. Chem. Soc., (1925), 127, 819) under argon inchloroform. The mixture is heated to reflux for 3 h. It is concentrated,the residue is taken up in ice-cold water and extracted three times withether, and the combined organic phases are dried and again concentratedin vacuo.

The resulting crude product is dissolved in 50 ml of anhydroustetrahydrofuran, mixed with 1 g of palladium on carbon (5% palladium)and hydrogenated under atmospheric pressure overnight. After working upby filtration and concentration, because conversion is incomplete thehydrogenation is repeated with 1.6 g of Pd/C (5% Pd) in 50 ml ofanhydrous tetrahydrofaran under atmosphenc pressure overnight.

This procedure is repeated once more.

1.90 g (98%) of 3,3-diethylcyclohexanone are obtained in this way,acording to GC-MS as 97% pure product, whch is reacted further as such.

985 mg (about 25 mmol) of sodium hydride (60%) are introduced into argoninto a reaction flask, the oil is removed with petroleum ether, and 15ml of diethyl carbonate are added. Then one drop of ethanol is added tothe resulting suspension, and the 1.90 g (12.3 mmol) of3,3-diethylcyclohexanone obtained above, dissolved in about 10 ml ofdiethylcarbonate, are slowly added dropwise. The mixture is stirred atnormal temperature overnight, during which slow evolution of hydrogen isobservable.

For working up, 30 g of ice and about 100 ml of water are slowly addedto the reaction mixture, and then the pH is adjusted to 5 with about 6ml of concentrated acetic acid.

The resulting solution is extracted three times with diethyl ether. Thecombined organic phases are washed twice with cold saturated sodiumbicarbonate solution and once with saturated brine and dried overmagnesium sulfate. The solution is then concentrated to about 5 ml invacuo in a rotary evaporator.

Kugelrohr distillation affords 1.37 g (49%) of the target compound insufficient purity for the next stages.

¹H-NMR (200 MHz, CDCl₃): the compound is substantially enolized:δ=0.7-0.95 (m, 6H), 1.13-1.5 (m, 9H), 2.04 (s, broad, 2H), 2.1-2.3 (m,2H), 4.12-4.28 (m, 2H), 12.20 (s, broad, 1H).

EXAMPLE I-13 Ethyl (6-oxo-spiro[3.5]non-7-yl)-carboxylate

5.00 g (36.7 mmol) of spiro[3.5]non-7-en-6-one (Paulsen, H. et al.,Angew. Chem., Int. Ed. (1999), 38, 3373) are introduced into 100 ml ofethylene glycol dimethyl 5 ether, and about 300 mg of Pd/C (5% Pd) areadded. Hydrogenation is carried out under atmospheric pressureovernight.

For working up, the catalyst is removed by filtration throughkieselguhr, and the filtrate is concentrated in vacuo.

5.21 g (91% pure according to GC analysis, equivalent to 93% yield ofproduct) of spiro[3.5]nonan-6-one are obtained in this way.

One third of 5.00 g (36.2 mmol) of spiro[3.5]nonan-6-one dissolved indiethyl carbonate is added dropwise to a suspension of 2.89 g (60%,approx. 72 nunol) of sodium hydride in diethyl carbonate under argon.Only after addition of a little THF/pentane to activate the sodiumhydride does a gentle but continuous evolution of hydrogen start. Theremainder of the ketone is slowly added in portions distributed over theday. The mixture is then stirred at normal temperature overnight.

For working up, 20 g of ice and about 100 ml of water are slowly addedto the reaction mixture. There is initial formation of a viscous sludgewhich slowly dissolves over time. A pH of 5 is adjusted with approx. 10ml of concentrated acetic acid.

The resulting solution is extracted three times with diethyl ether. Thecombined organic phases are washed twice with cold saturated sodiumbicarbonate solution and once with saturated brine and dried overmagnesium sulfate. After concentration in a rotary evaporator, about 70ml of liquid remains.

For purification, initially excess diethyl carbonate is distilled out bydistillation at 50-60° C. and 70-80 mbar.

The residue is subjected to short-path distillation with Vigreuxattachment at about 0.25 mbar and 60-70° C.

3.71 g (49%) of the target compound are obtained in sufficient purityfor the following stages in this way.

¹H-NMR (200 MHz, DMSO-d₆): the compound is substantially enolized:δ=1.11-1.29 (m, 3H), 1.50-2.05 (m, 8H), 2.17 (t, broad, J=6 Hz, 2H),2.31 (s, broad, 2H), 4.0-4.25 (m, 2H), 12.11 (s, broad, 1H).

EXAMPLE I-14 Ethyl (2-oxo-spiro[5.5]undec-3-yl)carboxylate

Under argon, 1.11 g (27.7 mmol) of sodium hydride (60%) are introducedinto a flask, the oil is removed with petroleum ether and 15 ml ofdiethyl carbonate are added. One drop of ethanol is added to theresulting suspension, and 2.30 g (13.8 mmol) of spiro[5.5]undecan-2-one(De Jongh, H. A. P. and Wynberg, K., Tetrahedron (1964), 20, 2553)dissolved in about 10 ml of diethyl carbonate are slowly added dropwise.The mixture is stirred at normal temperature overnight, during whichslow evolution of hydrogen is observable.

For working up, 30 g of ice and about 100 ml of water are slowly addedto the reaction mixture, and then the pH is adjusted to 5 with about 6ml of concentrated acetic acid.

The resulting solution is extracted three times with diethyl ether. Thecombined organic phases are washed twice with cold saturated sodiumbicarbonate solution and once with saturated brine and dried overmagnesium sulfate. This is followed by evaporation to about 5 ml invacuo in a rotary evaporator.

Kugelrohr distillation affords 2.43 g (74%) of the target compound.

¹H-NMR (200 MHz, CDCl₃): the compound is substantially enolized:δ=1.2-1.6 (m, 15H), 2.11 (s, broad, 2H), 2.13-2.28 (m, 2H), 4.11-4.29(m, 2H), 12.19 (s, broad, 1H).

The following are prepared in analogy to the method of Example I-1:

EXAMPLE I-15 6-Bromo-3,3-diethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (EI+): 350 (M);

¹H-NMR (300 MHz, CDCl₃): δ=0.85 (t, 6H); 1.37 (mc, 4H); 1.64 (t, 2H);2.45 (s, br, 2H); 2.65 (t, br, 2H); 7.56 (dd, 1H); 7.67 (d, 1H); 8.35(d, 1H).

EXAMPLE I-166-Bromo-3-spirohexyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (CI+): 363 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=1.3-1.6 (m, 10H); 1.70 (t, 2H); 2.51 (s, br,2H); 2.66 (t, br, 2H); 7.56 (dd, 1H); 7.66 (d, 1H); 8.34 (d, 1H).

The following are prepared in analogy to the method of Example I-5:

EXAMPLE I-173,3-Dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carbonitrile

MS (CI+): 270 (M+H);

¹H-NMR (300 MHz, DMSO): δ=0.99 (s, 6H); 1.58 (t, 2H); 2.45-2.6 (m, 4H);7.94 (dd, 1H); 8.42 (d, 1H); 8.50 (d, 1H).

EXAMPLE I-183,3-Diethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carbonitrile

MS (CI+): 298 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=0.86 (t, 6H); 1.38 (mc, 4H); 1.66 (t, 2H);2.49 (s, br, 2H); 2.67 (t, br, 2H); 7.67 (dd, 1H); 7.83 (d, 1H); 8.58(d, 1H).

EXAMPLE I-199-Oxo-3-spirobutyl-2,3,4,9-tetrahydro-1-thioxanthene-6-carbonitrile

MS (CI+): 282 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=1.80-2.05 (m, 8H); 2.72 (tt, 2H); 2.76 (s,br, 2H); 7.68 (dd, 1H); 7.84 (d, 1H); 8.57 (d, 1H).

EXAMPLE I-209-Oxo-3-spirohexyl-2,3,4,9-tetrahydro-1H-thioxanthene-6-carbonitrile

MS (EI+): 309 (M);

¹H-NMR:(300 MHz, CDCl₃): δ=1.35-1.6 (m, 10H); 1.72 (t, 2H); 2.55 (s, br,2H); 2.69 (t, br, 2H); 7.67 (dd, 1H); 7.83 (d, 1H); 8.58 (d, 1H).

EXAMPLE I-2112-Oxo-6,7,8,9,10,11-hexahydro-12H-cycloocta[b]thiochromene-3-carbonitrile

The product is purified by crystallization from acetone.

MS (CI+): 270 (M+H);

¹H-NMR (300 MHz, DMSO): δ=1.30-1.52 (m, 4H); 1.53-1.65 (m, 2H);1.70-1.85 (m, 2H); 2.90 (m, 4H); 7.94 (dd, 1H); 8.43 (d, 1H); 8.50 (d,1H).

The following are prepared in analogy to the method of Example I-11:

EXAMPLE I-223,3-Dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carboxylic acid

MS (ESI+): 289 (M+H);

HPLC: R_(t)=4.57 min;

¹H-NMR (200 MHz, DMSO): δ=0.99 (s, 6H); 1.58 (t, 2H); 2.45-2.65 (m, 4H);8.02 (dd, 1H); 8.29 (d, 1H); 8.41 (d, 1H); 13.58 (s, br, 1H).

EXAMPLE I-2312-Oxo-6,7,8,9,10,11-hexahydro-12H-cycloocta[b]thiochromene-3-carboxylicacid

98 mg (1.48 mmol) of potassium hydroxide powder are added under an argonatmosphere to 200 mg (0.74 mmol) of12-oxo-6,7,8,9,10,11-hexahydro-12H-cycloocta[b]thiochromene-3-carbonitrilein 10 ml of 1,2-ethanediol, and the mixture is stirred at 120° C.overnight. After cooling, a little water is added, and the mixture isthen acidified to pH 2 with 1N hydrochloric acid. The precipitate isfiltered off and washed with water.

160 mg (75%) of the target compound are obtained in this way.

HPLC: R_(t)=4.38 min;

¹H-NMR (300 MHz, THF): δ=1.40-1.60 (m, 4H); 1.68 (mc, 2H); 1.70-1.85(mc, 2H); 2.92 (mc, 4H); 8.04 (dd, 1H); 8.26 (d, 1H); 8.48 (d, 1H);11-13 (br, 1H).

EXAMPLE I-246-(Cyanomethyl)-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

300 mg (1.02 mmol) of6-(chloromethyl)-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one,80.1 mg (1.23 mmol) of potassium cyanide and 13.5 mg (0.05 mmol) of18-crown-6 are mixed in 1.00 ml of N,N-dimethylformamide under argon andthen stirred at a bath temperature of 40° C. overnight. For working up,the mixture is dried with magnesium sulfate. The solvent is concentratedin vacuo, and the residue is chromatographed (preparative HPLC,acetonitrile/water 50:50-95:5). 105 mg (36%) of the target compound areobtained in this way.

MS (ESI+): 284 (M+H);

HPLC: R_(t)=4.76 min;

¹H-NMR (300 MHz, DMSO): δ=0.99 (s, 6H); 1.58 (t, 2H); 2.45-2.65 (m, 4H);4.21 (s, 2H); 7.53 (d, 1H); 7.73 (s, 1H); 8.34 (d, 1H).

EXAMPLE I-25(3,3-Dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)acetic acid

109 mg (0.38 mmol) of6-(cyanomethyl)-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one aresuspended in 70% strength sulfuric acid and stirred at a bathtemperature of 120° C. under argon. After the reaction is complete(about 3 hours), the mixture is allowed to cool and is added toice-water. The precipitated solid is filtered off with suction, washedwith water and dried in vacuo. 109 mg (93%) of the target compound areobtained in this way.

MS (ESI+): 303 (M+H);

HPLC: R_(t)=4.47 min;

¹H-NMR (200 MHz, DMSO): δ=0.99 (s, 6H); 1.57 (t, 2H); 2.4-2.65 (m, 4H);3.74 (s, 2H); 7.46 (dd, 1H); 7.65 (s, br, 1H); 8.26 (d, 1H); 12.1-12.9(s, br, 1H).

EXEMPLARY EMBODIMENTS 1

The following were prepared in analogy to the method of Example I-1:

EXAMPLE 1-1 3-Ethyl-6-methoxy-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (EI+): 274 (M);

¹H-NMR (400 MHz, CDCl₃): δ=0.99 (t, J=7.5Hz; 3H); 1.34-1.44 (m, 3H);1.64-1.72 (m, 1H); 1.97-2.04 (m, 1H); 2.33-2.40 (m, 1H); 2.44-2.54 (m,1H); 2.69 (m, 1H); 2.86-2.93 (m, 1H); 3.88 (s, 3H); 6.88 (d, J=2.5; 1H);6.99-7.03 (dd, J=9 Hz, 2.5 Hz; 1H); 8.41 (d, J=9 Hz; 1H).

EXAMPLE 1-2 3-Ethyl-6-methyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (EI+): 258 (M);

¹H-NMR (300 MHz, CDCl₃): δ=0.99 (t, J=7.5Hz; 3H); 1.33-1.47 (m, 3H);1.64-1.76 (m, 1H); 1.98-2.07 (m, 1H); 2.34-2.42 (m, 1H); 2.44 (s, 3H);2.46-2.56 (m, 1H); 2.66-2.74 (m, 1H); 2.86-2.96 (m, 1H); 7.25-7.29 (m,2H); 8.38 (d, J=9 Hz; 1H).

EXAMPLE 1-33-Ethyl-6-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

0.50 g (1.86 mmol) of3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carbonitrile (ExampleI-5), 0.51 g (3.71 mmol) of triethylamrnonium hydrochloride and 0.24 g(3.71 mmol) of sodium azide are heated in toluene to 100° C. and stirredat this temperature overnight.

After a TLC check for completeness of conversion, the reaction mixtureis allowed to cool and added to 100 ml of water/20 ml of toluene,stirred vigorously for 10 min, acidified to about pH 3 with 5Nhydrochloric acid and stirred for a further 10 min, and the precipitatedsolid is filtered off with suction and washed twice with water. Theremaining crude product is dried and recrystallized fromcyclohexane/ethyl acetate approx. 1:40. 290 mg (50%) of the targetcompound are obtained in this way.

MS (CI+): 313 (M+H);

¹H-NMR (300 MHz, DMSO): δ=0.95 (t, J=7.5 Hz; 3H); 1.30-1.43 (m, 3H);1.60-1.74 (m, 1H); 1.92-2.02 (m, 1H); 2.33-2.47 (m, 2H); 2.72-2.82 (m,2H); 3.00-3.60 (m, b, 1H); 8.14-8.18 (dd, J=8.5 Hz, 1.5 Hz; 1H); 8.39(d, J=1.5 Hz; 1H), 8.47-8.50 (d, J=8.5 Hz; 1H).

The following were prepared in analogy to the method of Example 1-3:

EXAMPLE 1-43-(1H-Tetraazol-5-yl)-6,7,8,9,10,11-hexahydro-12H-cycloocta[b]thiochromen-12-one

MS (EI+): 312 (M);

¹H-NMR (200 MHz, DMSO): δ=1.30-1.43 (m, 4H); 1.54-1.66 (m, 2H);1.73-1.84 (m, 2H); 2.83-2.94 (m, 4H); 3.12-3.68 (m, b, 1H); 8.15-8.20(dd, J=8.5 Hz, 1.5 Hz; 1H); 8.43 (s, 1H), 8.49-8.53 (d, J=8.5 Hz; 1H).

EXAMPLE 1-53,3-Dimethyl-6-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (CI+): 313 (M+H);

¹H-NMR (200 MHz, DMSO): δ=1.00 (s, 6H); 1.59 (t, J=6.5 Hz; 2H);2.47-2.62 (m, 4H); 3.08-3.52 (s, b, 1H); 8.15-8.20 (dd, J=8.5 Hz, 1.5Hz, 1H); 8.40 (s, 1H); 8.50 (d, J=8.5 Hz; 1H).

EXAMPLE 1-63-Spirobutyl-6-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (ESI): 325 (M+H);

¹H-NMR (200 MHz, DMSO): δ=1.79-1.99 (m, 8H); 2.56-2.63 (t, J=6 Hz;2H);2.84 (s, 2H); 3.12-3.60 (s, b, 1H); 8.14-8.19 (dd, J=8.5 Hz, 1.5 Hz;1H); 8.41 (d, J=1.5 Hz; 1H); 8.47-8.51 (d, J=8.5 Hz; 1H).

EXAMPLE 1-73-Spirohexyl-6-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (EI+): 352 (M);

¹H-NMR (300 MHz, DMSO): δ=1.33-1.48 (m, 10H); 1.67 (t, J=6.5 Hz; 2H);2.56 (t, J=6.5 Hz; 2H); 2.61 (s, 2H); 3.17-3.45 (s, b, 1H); 8.15-8.19(dd, J=8.5 Hz, 1H); 8.40 (d, J=1.5 Hz; 1H); 8.48-8.51 (d, J=8.5 Hz; 1H).

EXAMPLE 1-83-Ethyl-6-[3-(1H-tetrazol-5-yl)phenyl]-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (ESI): 389 (M+H);

¹H-NMR (300 MHz, DMSO): δ=0.96 (t, J=7.5 Hz; 3H); 1.31-1.44 (m, 3H);1.62-1.74 (m, 1H); 1.93-2.02 (m, 1H); 2.34-2.53 (m, 2H); 2.72-2.82 (m,2H); 3.23-3.40 (s, b, 1H); 7.73-7.79 (t, J=8 Hz; 1H); 7.95-7.98 (dd,J=8.5 Hz, 1.5 Hz; 1H); 8.05 (d, J=8 Hz; 1H); 8.12 (d, J=8 Hz; 1H); 8.19.(d, J=1.5 Hz; 1H); 8.42-8.46 (m, 2H).

EXAMPLE 1-93-Ethyl-6-(2-methyl-2H-tetrazol-5-yl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

Under argon, 91.0 mg (0.29 mmol) of3-ethyl-6-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one(Example 1-3) are dissolved in 5 ml of DMF, and 95 mg (0.29 mmol) ofcesium carbonate are added. The mixture is heated at 60° C. for 1 h,cooled again to nonmal temperature and, after addition of 0.03 ml (0.45mmol) of iodomethane, left to stir at normal temperature overnight. Forworking up, about 10 ml of water and ethyl acetate are added to themixture, which is stirred for 5 min and added to 50 ml of water. Threemore extractions with ethyl acetate are carried out, and the combinedorganic phases are dried and concentrated in a rotary evaporator.

The crude product obtained in this way is fractionated and purified bypreparative HPLC.

54.9 mg (58%) of the target compound are obtained in this way.

MS (EI+): 326 (M);

¹H-NMR (300 MHz, CDCl₃): δ=1.00 (t, J=7.5 Hz; 3H); 1.38-1.49 (m, 3H);1.68-1.79 (m, 1H); 2.01-2.10 (m, 1H); 2.40-2.60 (m, 2H); 2.72-2.79 (m,1H); 2.91-2.97 (m, 1H); 4.44 (s, 3H); 8.17-8.21 (dd, J=8.5, 1.5 Hz; 1H);8.33 (d, J=1.5 Hz; 1H); 8.60 (d, J=8.5 Hz; 1H).

The byproduct isolated are:

5.2 mg (5.5%) of3-ethyl-6-(1-methyl-1H-tetrazol-5-yl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

¹H-NMR (400 MHz, CDCl₃): δ=1.01 (t, J=7.5Hz; 3H); 1.38-1.49 (m, 3H);1.70-1.79 (m, 1H); 2.03-2.11 (m, 1H); 2.42-2.61 (m, 2H); 2.73-2.80 (m,1H); 2.91-2.97 (m, 1H); 4.25 (s, 3H); 7.75-7.77 (dd, J=8.5, 1.5 Hz; 1H);8.01 (d, J=1.5 Hz; 1H); 8.67 (d, J=8.5 Hz; 1H).

EXAMPLE 1-103-Ethyl-6-(2-thienyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

100 mg (0.31 mmol) of6-bromo-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one (Example I-1)are introduced into 2.0 ml of 1,2-dimethoxyethane and, after addition of47.5 mg (0.37 mmol) of thiophene-2-boronic acid, 0.34 ml (0.68 mmol) of2M aqueous sodium carbonate solution and 10 mg ofdichlorobis(triphenylphosphine)palladium(II), heated to reflux for about2 h until the reaction is complete.

After cooling, the reaction mixture is filtered through a cartridge with1 g of silica gel, and the eluate is concentrated and separated bypreparative HPLC.

Drying of the product fractions in vacuo results in 76.8 mg (76%) of thetarget compound.

MS (CI+): 327 (M+H);

¹H-NMR (200 MHz, CDCl₃): δ=1.00 (t, J=7.5 Hz; 3H); 1.35-1.51 (m, 3H);1.62-1.81 (m, 1H); 1.98-2.11 (m, 1H); 2.34-2.61 (m, 2H); 2.66-2.79 (m,1H); 2.84-3.00 (m, 1H); 7.11-7.16 (dd, J=5 Hz, 3.5 Hz; 1H); 7.38-7.41(dd, J=5 Hz, 1 Hz; 1H); 7.45-7.47 (dd, J=3.5Hz, 1Hz; 1H); 7.67-7.72 (m,2H); 8.47-8.51 (m, 1H).

The following were prepared in analogy to the method of Example 1-10:

EXAMPLE 1-113-(2-Thienyl)-6,7,8,9,10,11-hexahydro-12H-cycloocta[b]thiochromen-12-one

MS (CI+): 327 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=1.40-1.55 (m, 4H); 1.69-1.77 (m, 2H);1.81-1.89 (m, 2H); 2.84-2.88 (m, 2H); 2.93-2.97 (m, 2H); 7.12-7.15 (dd,J=5 Hz, 4 Hz; 1H); 7.39-7.40 (dd, J=5 Hz, 1Hz; 1H); 7.46-7.47 (dd,J=3.5Hz, 1Hz; 1H); 7.70-7.74 (m, 2H); 8.49-8.52 (m, 1H).

EXAMPLE 1-123,3-Dimethyl-6-(2-thienyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (EI+): 326 (M);

¹H-NMR (200 MHz, CDCl₃): δ=1.05 (s, 6H); 1.64 (t, J=6.5 Hz; 2H); 2.48(s, 2H); 2.73 (t, J=6.5 Hz; 2H); 7.11-7.16 (dd, J=5 Hz, 3.5Hz; 1H);7.38-7.41 (dd, J=5 Hz, 1 Hz; 1H); 7.45-7.48 (dd, J=3.5 Hz, 1Hz; 1H);7.68-7.74 (m, 2H); 8.48-8.52 (m, 1H).

EXAMPLE 1-133-Spirobutyl-6-(2-thienyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (CI+): 339 (M+H);

¹H-NMR(300 MHz, CDCl₃): δ=1.80-2.00 (m, 8H); 2.68-2.81 (m, 4H);7.12-7.15 (dd, J=5 Hz, 3.5 Hz; 1H); 7.38-7.40 (dd, J=5 Hz, 1 Hz; 1H);7.45-7.47 (m, 1H); 7.68-7.71 (m, 2H); 8.47-8.50 (m, 1H).

EXAMPLE 1-143-Ethyl-6-(4-methyl-2-thienyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (CI+): 341 (M+H);

¹H-NMR (200 MHz, CDCl₃): δ=1.00 (t, J=7.5 Hz; 3H); 1.34-1.50 (m, 3H);1.61-1.79 (m, 1H); 1.98-2.12 (m, 1H); 2.31 (s, 3H); 2.38-2.63 (m, 2H);2.65-2.78 (m, 1H); 2.85-2.99 (m, 1H); 6.97 (s, 1H); 7.28 (m, 1H);7.64-7.69 (m, 2H); 8.45-8.49 (m, 1H).

EXAMPLE 1-156-(5-Acetyl-2-thienyl)-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (ESI): 369 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=1.00 (t, J=7.5 Hz; 3H); 1.35-1.49 (m, 3H);1.67-1.77 (m, 1H); 2.01-2.10 (m, 1H); 2.37-2.54 (m, 2H); 2.59 (s, 3H);2.69-2.78 (m, 1H); 2.88-2.97 (m, 1H); 7.45 (d, J=4 Hz; 1H); 7.69-7.75(m, 3H); 8.52 (d, J=8.5 Hz; 1H).

EXAMPLE 1-163-Ethyl-6-(3-thienyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (CI+): 327 (M+H);

¹H-NMR (300 MHz, CDC₁₃): δ=1.00 (t, J=7.5Hz; 3H); 1.37-1.48 (m, 3H);1.66-1.78 (m, 1H); 2.00-2.09 (m, 1H); 2.37-2.58 (m, 2H); 2.67-2.76 (m,1H); 2.88-2.98 (m, 1H); 7.42-7.47 (m, 2H); 7.62 (m, 1H); 7.68-7.71 (m,2H); 8.51 (m, 1H).

EXAMPLE 1-17 3-Ethyl-6-phenyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (CI+): 321 (M+H);

¹H-NMR (200 MHz, CDCl₃): δ=1.00 (t, J=7.5 Hz; 3H); 1.33-1.51 (m, 3H);1.62-1.80 (m, 1H); 1.99-2.12 (m, 1H); 2.35-2.64 (m, 2H); 2.68-2.79 (m,1H); 2.87-3.02 (m, 1H); 7.41-7.53 (m, 3H); 7.64-7.73 (m, 4H); 8.53-8.58(m, 1H).

EXAMPLE 1-186-Phenyl-3-spirobutyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (CI+): 333 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=1.80-2.04 (m, 8H); 2.72-2.76 (m, 4H);7.39-7.52 (m, 3H); 7.63-7.71 (m, 4H); 8.54-8.57 (m, 1H).

EXAMPLE 1-193-Ethyl-6-(4-methylphenyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (CI+): 335 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=1.00 (t, J=7.5 Hz; 3H); 1.35-1.48 (m, 3H);1.66-1.78 (m, 1H); 2.00-2.09 (m, 1H); 2.42 (s, 3H); 2.43-2.59 (m, 2H);2.68-2.77 (m, 1H); 2.88-2.98 (m, 1H); 7.28-7.30 (d, J=8 Hz; 2H);7.54-7.57 (d, J=8 Hz; 2H); 7.67-7.70 (m, 2H); 8.52-8.55 (m, 1H).

EXAMPLE 1-20N-[3-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)phenyl]acetamide

MS (CI+): 378 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=1.00 (t, J=7.5 Hz; 3H); 1.36-1.48 (m, 3H);1.66-1.77 (m, 1H); 2.00-2.09 (m, 1H); 2.24 (s, 3H); 2.37-2.58 (m, 2H);2.68-2.76 (m, 1H); 2.88-2.98 (m, 1H); 7.36-7.58 (m, 4H); 7.64-7.69 (m,2H); 7.84 (s, 1H); 8.53 (m, 1H).

EXAMPLE 1-213-Ethyl-6-(4-methoxyphenyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (CI+): 351 (M+H);

¹H-NMR (200 MHz, CDCl₃): δ=1.00 (t, J=7.5 Hz; 3H); 1.35-1.51 (m, 3H);1.62-1.79 (m, 1H); 1.98-2.11 (m, 1H); 2.34-2.62 (m, 2H); 2.67-2.79 (m,1H); 2.86-3.01 (m, 1H); 3.87 (s, 3H); 6.99-7.03 (m, 2H); 7.57-7.69 (m,4H); 8.50-8.55 (m, 1H).

EXAMPLE 1-226-(4-Methoxyphenyl)-3-spirobutyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (CI+): 363 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=1.80-2.03 (m, 8H); 2.71-2.76 (m, 4H); 3.87(s, 3H); 7.00-7.03 (m, 2H); 7.58-7.68 (m, 4H); 8.50-8.53 (m, 1H).

EXAMPLE 1-233-Ethyl-6-(3-nitrophenyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one-12-one

MS (CI+): 366 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=1.01 (t, J=7.5 Hz; 3H); 1.37-1.50 (m, 3H);1.68-1.79 (m, 1H); 2.02-2.11 (m, 1H); 2.40-2.61 (m, 2H); 2.71-2.79 (m,1H); 2.89-2.99 (m, 1H); 7.65-7.75 (m, 3H); 7.97-8.01 (m, 1H); 8.27-8.30(m, 1H); 8.52 (m, 1H); 8.60-8.63 (m, 1H).

EXAMPLE 1-246-(4-Chlorophenyl)-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (CI+): 355 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=1.00 (t, J=7.5 Hz; 3H); 1.37-1.49 (m, 3H);1.66-1.78 (m, 1H); 2.01-2.10 (m, 1H); 2.38-2.59 (m, 2H); 2.69-2.77 (m,1H); 2.89-2.98 (m, 1H); 7.43-7.48 (m, 2H); 7.56-7.61 (m, 2H); 7.63-7.67(m, 2H); 8.54-8.57 (m, 1H).

EXAMPLE 1-253-Ethyl-6-[4-(hydroxymethyl)phenyl]-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (CI+): 351 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=0.95 (t, J=7.5 Hz; 3H); 1.28-1.43 (m, 3H);1.60-1.72 (m, 1H); 1.92-2.01 (m, 1H); 2.32-2.47 (m, 2H); 2.70-2.78 (m,2H); 4.57 (d, J=5.5 Hz; 2H); 5.29 (t, J=5.5 Hz; 1H); 7.46 (d, J=8 Hz;2H); 7.80 (d, J=8.5 Hz; 2H); 7.85-7.89 (dd, J=8.5 Hz, 1.5 Hz; 1H); 8.07(d, J=1.5 Hz; 1H); 8.37 (m, 1H).

EXAMPLE 1-264-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)benzonitrile

MS (EI+): 345 (M);

¹H-NMR (200 MHz, CDCl₃): δ=1.00 (t, J=7.5 Hz; 3H); 1.36-1.52 (m, 3H);1.63-1.82 (m, 1H); 1.99-2.13 (m, 1H); 2.36-2.64 (m, 2H); 2.68-2.81 (m,1H); 2.87-3.02 (m, 1H); 7.65-7.82 (m, 6H); 8.57-8.61 (m, 1H).

EXAMPLE 1-273-(3,3-Dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)benzonitrile

MS (EI+): 345 (M);

¹H-NMR (200 MHz, CDCl₃): δ=1.06 (s, 6H); 1.65 (t, J=6.5 Hz; 2H); 2.51(s, 2H); 2.75 (t, J=6.5 Hz; 2H); 7.57-7.74 (m, 4H); 7.85-7.93 (m, 2H);8.58-8.62 (m, 1H).

EXAMPLE 1-283-(9-Oxo-3-spirobutyl-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)benzomitrile

MS (CI+): 358 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=1.81-2.01 (m, 8H); 2.72-2.78 (m, 4H);7.58-7.73 (m, 4H); 7.86-7.90 (m, 1H); 7.93 (s, 1H); 8.59 (d, J=8.5 Hz;1H).

EXAMPLE 1-293-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)benzonitrile

MS (CI+): 346 (M+H);

¹H-NMR (200 MHz, CDCl₃): δ=1.01 (t, J=7.5 Hz; 3H); 1.34-1.52 (m, 3H);1.64-1.82 (m, 1H); 2.01-2.13 (m, 1H); 2.36-2.63 (m, 2H); 2.68-2.81 (m,1H); 2.87-3.02 (m, 1H); 7.57-7.73 (m, 4H); 7.86-7.93 (m, 2H); 8.57-8.62(m, 1H).

EXAMPLE 1-303-Ethyl-6-(3-pyridinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (DCI+): 322 (M+H);

¹H-NMR (200 MHz, CDCl₃): δ=1.01 (t, J=7.5 Hz; 3H); 1.36-1.52 (m, 3H);1.65-1.81 (m, 1H); 1.99-2.13 (m, 1H); 2.36-2.64 (m, 2H); 2.68-2.82 (m,1H); 2.87-3.02 (m, 1H); 7.39-7.45 (m, 1H); 7.66-7.70 (m, 2H); 7.92-7.98(m, 1H); 8.58-8.6 (m, 2H); 8.92 (m, 1H).

EXAMPLE 1-313,3-Dimnethyl-6-(3-pyridinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (CI+): 322 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=1.06 (s, 6H); 1.65 (t, J=6.5 Hz; 2H); 2.50(s, 2H); 2.75 (t, J=6.5 Hz; 2H); 7.40-7.45 (m, 1H); 7.67-7.69 (m, 2H);7.93-7.97 (m, 1H); 8.61 (dd, J=8 Hz, 1 Hz; 1H); 8.67 (dd, J=4.5 Hz, 1.5Hz; 1H); 8.90 (m, 1H).

EXAMPLE 1-326-(3-Pyridinyl)-3-spirobutyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (CI+): 334 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=1.81-2.02 (m, 8H); 2.70-2.77 (m, 4H);7.40-7.45 (m, 1H); 7.66-7.70 (m, 2H); 7.92-7.96 (m, 1H); 8.59 (d, J=8.5Hz; 1H); 8.66-8.68 (dd, J=4.5 Hz, 1.5 Hz; 1H); 8.91 (d, J=2 Hz; 1H).

EXAMPLE 1-333-Ethyl-6-(4-pyridinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (CI+): 322 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=1.01 (t, J=7.5 Hz; 3H); 1.38-1.49 (m, 3H);1.68-1.79 (m, 1H); 2.02-2.11 (m, 1H); 2.39-2.59 (m, 2H); 2.71-2.78 (m,1H); 2.89-2.98 (m, 1H); 7.55-7.58 (m, 2H); 7.70-7.75 (m, 2H); 8.59-8.16(d, J=8.5 Hz; 1H); 8.72 (m, 2H).

EXAMPLE 1-343-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-1,2,4-oxadiazol-5(4H)-one

100 mg (0.33 mmol) of3-ethyl-N′-hydroxy-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carboximidamide(Example I-7) and 0.03 ml (0.36 mmol) of pyridine are dissolved in 2 mlof DMF under argon. The solution is cooled to about 0° C., 0.06 ml (0.33mmol) of 2-ethylhexyl chlorofonnate is added dropwise, and the mixtureis stirred at about 0° C. for 30 min. The mixture is put then put intoabout 50 ml of water, extracted three times with 50 ml of ethyl acetateeach time, and the organic phases are combined and dried andconcentrated in a rotary evaporator.

The remaining residue is taken up in xylene and heated to boiling for 8h.

The suspension formed after standing at normal temperature overnight ismixed with 20 ml of diethyl ether, the mixture is stirred for 5 min, andthen the solid is filtered off, thoroughly washed with about 30 ml ofdiethyl ether and dried. 68.2 mg (63%) of the target compound areobtained in this way.

MS (ESI): 329 (M+H);

¹H-NMR (300 MHz, DMSO): δ=0.95 (t, J=7.5 Hz; 3H); 1.34-1.44 (m, 3H);1.61-1.73 (m, 1H); 1.92-2.01 (m, 1H); 2.33-2.46 (m, 2H); 2.70-2.82 (m,2H); 7.93 (m, 1H); 8.17 (m, 1H); 8.44 (m, 1H); 13.15 (s, b, 1H).

The following were prepared in analogy to the method of Example 1-34:

EXAMPLE 1-353-(12-Oxo-6,8,9,10,11,12-hexahydro-7H-cycloocta[b]thiochromen-3-yl)-1,2,4-oxadiazol-5(4H)-one

MS (ESI): 329 (M+H);

¹H-NMR (300 MHz, DMSO): δ=1.34-1.49 (m, 4H); 1.54-1.64 (m, 2H);1.74-1.82 (m, 2H); 2.86-2.93 (m, 4H); 3.25-3.36 (s, b, 1H); 7.93-7.97(dd, J=8.5 Hz, 1.5 Hz, 1H); 8.19 (d, J=1.5 Hz; 1H); 8.46 (d, J=8.5 Hz;1H).

EXAMPLE 1-363-(3,3-Dimnethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-1,2,4-oxadiazol-5(4H)-one

MS (ESI): 329 (M+H);

¹H-NMR (200 MHz, DMSO): δ=1.00 (s, 6H); 1.59 (t, J=6.5 Hz; 2H);2.49-2.62 (m, 3H); 7.92-7.97 (dd, J=8.5 Hz, 1.5 Hz, 1H); 8.17 (s, 1H);8.45 (d, J=8.5 Hz; 1H), 13.15 (s, b, 1H).

EXAMPLE 1-372-[(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)oxy]acetamide

Under argon, 50 mg (0.19 mmol) of3-ethyl-6-hydroxy-1,2,3,4-tetrahydro-9H-thioxanthen-9-one (Example I-6),53 mg (0.38 mmol) of bromoacetamide, 188 mg (0.58 mmol) of cesiumcarbonate and about 3 mg of potassium iodide are mixed in 3 ml of2-butanone, and the resulting reaction mixture is heated to refluxovernight.

For working up, 30 ml of ethyl acetate are added to the mixture, theinsoluble solid is removed, and the filtrate is concentrated in a rotaryevaporator and purified by preparative HPLC.

37.7 mg (62%) of the target compound are obtained in this way.

MS (ESI): 318 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=0.99 (m, 3H); 1.34-1.46 (m, 3H); 1.72-1.78(m, 1H); 1.97-2.07 (m, 1H); 2.33-2.56 (m, 2H); 2.64-2.73 (m, 1H);2.84-2.94 (m, 1H); 4.58 (d, 2H); 5.70 (s, 1H); 6.50 (s, 1H); 6.93 (m,1H); 7.05 (m, 1H); 8.46 (m, 1H).

The following were prepared in analogy to the method of Example 1-37.

EXAMPLE 1-38[(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-oxy]-acetonitrile

MS (CI+): 300 (M+H);

¹H-NMR (200 MHz, CDCl₃): δ=0.99 (t, J=7.5 Hz; 3H); 1.34-1.50 (m, 3H);1.62-1.76 (m, 1H); 1.96-2.09 (m, 1H); 2.30-2.58 (m, 2H); 2.63-2.74 (m,1H); 2.83-2.97 (m, 1H); 4.86 (s, 2H); 7.00 (d, J=2.5 Hz; 1H); 7.06-7.12(dd, J=9 Hz, 2.5 Hz; 1H); 8.49 (d, J=9 Hz; 1H).

EXAMPLE 1-39 6-Ethoxy-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (CI+): 289 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=0.99 (t, J=7.5 Hz; 3H); 1.34-1.48 (m, 6H);1.66-1.74 (m, 1H); 1.98-2.07 (m, 1H); 2.32-2.56 (m, 2H); 2.63-2.71 (m,1H); 2.86-2.96 (m, 1H); 4.08-4.13 (quart., J=7 Hz; 2H); 6.88 (d, J=2.5Hz; 1H); 6.99-7.03 (dd, J=9 Hz, 2.5 Hz; 1H); 8.39-8.43 (d, J=9 Hz; 1H).

EXAMPLE 1-40 3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-ylmethanesulfonate

70 mg (0.27 mmol) of3-ethyl-6-hydroxy-1,2,3,4-tetrahydro-9H-thioxanthen-9-one (Example I-6)are introduced under argon into dichloromethane, and initially 43 mg(0.13 mmol) of tetra-n-butylammonium bromide and 120 mg of 45 percentstrength sodium hydroxide solution and, after 10 min 34 mg (0.30 mmol)of methanesulfonyl chloride are added. After stirring at normaltemperature for 1.5 h, for working up 0.5 ml of buffer of pH 7 is added,the resulting mixture is sucked through a cartridge with 1 g ofExtrelut/silica gel, the cartridge is washed with ethyl acetate, and theeluate is concentrated. Purification of the crude product by preparativeHPLC affords 62.9 mg (69%) of the target compound.

MS (CI+): 339 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=0.99 (t, J=7.5 Hz; 3H); 1.36-1.48 (m, 3H);1.64-1.77 (m, 1H); 2.00-2.09 (m, 1H); 2.36-2.57 (m, 2H); 2.67-2.76 (m,1H); 2.86-2.95 (m, 1H); 3.22 (s, 3H); 7.32-7.36 (dd, J=9 Hz, 2.5 Hz;1H); 7.48 (d, J=2.5 Hz; 1H); 8.54-8.57 (d, J=9 Hz; 1H).

The following were prepared in analogy to the method of Example 1-40:

EXAMPLE 1-41 3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl4,4,4-trifluoro-1-butane-sulfonate

MS (CI+): 435 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=0.99 (t, J=7.5 Hz; 3H); 1.36-1.48 (m, 3H);1.64-1.77 (m, 1H); 2.00-2.09 (m, 1H); 2.26-2.58 (m, 6H); 2.68-2.76 (m,1H); 2.86-2.95 (m, 1H); 3.41 (t, J=7 Hz; 2H); 7.30-7.33 (dd, J=9 Hz, 2.5Hz; 1H); 7.45 (d, J=2.5 Hz; 1H); 8.53-8.56 (d, J=9 Hz; 1H).

EXAMPLE 1-423-[(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)oxy]benzonitrile

Under argon, 250 mg (0.77 mmol) of6-bromo-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one (Example I-1),276 mg (2.32 mmol) of 3-cyanophenol and 214 mg (1.55 mmol) of potassiumcarbonate are introduced into pyridine and briefly heated to 140° C. Themixture is allowed to cool slightly again, and 147 mg (0.77 mmol) ofcopper(I) iodide are added. The mixture is then stirred at about 140° C.for 48 h.

For working up, the pyridine is removed in a rotary evaporator by twicetaking up the initially remaining residue in toluene and againevaporating. The residue is taken up in ethyl acetate, and the mixtureis extracted with 5N hydrochloric acid and washed with sodiumbicarbonate solution and water. After drying over magnesium sulfate andconcentrating, the oily crude product is absorbed onto 0.5 g of silicagel and purified by column chromatography on about 40 g of silica gelwith a cyclohexane/ethyl acetate mobile phase gradient from 20:1 to 2:1.95.3 mg (34.1%) of the target compound are obtained in this way.

MS (CI+): 362 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=0.99 (t, J=7.5 Hz; 3H); 1.34-1.47 (m, 3H);1.64-1.76 (m, 1H); 1.98-2.07 (m, 1H); 2.34-2.57 (m, 2H); 2.64-2.73 (m,1H); 2.86-2.96 (m, 1H); 7.03 (d, J=2 Hz; 2H); 7.08-7.11 (m, 1H);7.28-7.37 (m, 1H); 7.47-7.54 (m, 2H); 8.50-8.53 (m, 1H).

The following were prepared in analogy to the method of Example 1-42:

EXAMPLE 1-433-[(3,3-Dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)oxy]benzonitrile

MS (EI+): 361 (M);

¹H-NMR (300 MHz, CDCl₃): δ=1.04 (s, 6H); 1.63 (t, J=6.5 Hz; 2H); 2.45(s, 2H); 2.71 (t, J=6.5 Hz; 2H); 7.03 (d, J=2.5 Hz; 1H); 7.08-7.12 (dd,J=9 Hz, 2.5 Hz; 1H); 7.29-7.35 (m, 2H); 7.47-7.52 (m, 2H); 8.52 (d, J=9Hz; 1H).

The following are prepared in analogy to the method of Example 1-3:

EXAMPLE 1-443,3-Diethyl-6-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

HPLC: R_(t)=4.95 min;

¹H-NMR (400 MHz, DMSO): δ=0.82 (t, 6H); 1.33 (mc, 4H); 1.60 (t, 2H);2.45-2.60 (m, 4H); 3.1-3.6 (s, b, 1H); 8.17 (dd, 1H); 8.40 (s, 1H); 8.49(d, 1H).

The following are prepared in analogy to the method of Example 1-10:

EXAMPLE 1-453,3-Diethyl-6-(2-thienyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

HPLC: R_(t)=7.05 min;

MS (ESI+): 355 (M+H);

¹H-NMR (300 MHz, CDCl₃): δ=0.83 (t, 6H); 1.2-1.5 (m, 4H); 1.65 (t, 2H);(s, br, 2H); 2.67 (t, 2H); 7.14 (dd, 1H); 7.40 (dd, 1H); 7.46 (dd, 1H);7.69 (s, 1H); 7.71 (dd, 1H); 8.49 (d, 1H).

EXAMPLE 1-466-(2-Thienyl)-3-spirohexyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (EI+): 366 (M);

HPLC: R_(t)=6.55 min;

¹H-NMR (200 MHz, CDCl₃): δ=1.3-1.6 (m, 10H); 1.71 (t, 2H); 2.53 (s, br,2H); 2.69 (t, br, 2H); 7.14 (dd, 1H); 7.40 (dd, 1H); 7.46 (dd, 1H);7.65-7.75 (m, 2H); 8.49 (d, 1H).

EXAMPLE 1-476-(3-Cyanophenyl)-3,3-diethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (ESI+): 374 (M+H);

HPLC: R_(t)=5.59 min;

¹H-NMR (300 MHz, CDCl₃): δ=0.87 (t, 6H); 1.23-1.52 (m, 4H); 1.67 (t,2H); 2.50 (s, br, 1H); 2.69 (t, 2H); 7.55-7.75 (m, 4H); 7.88 (dt, 1H);7.90-7.95 (m, 1H); 8.60 (d, 1H).

EXAMPLE 1-486-(3-Cyanophenyl)-3-spirohexyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

MS (EI+): 385 (M);

HPLC: R_(t)=6.11 min;

¹H-NMR (200 MHz, CDCl₃): δ=1.35-1.6 (m, 10H); 1.73 (t, 2H); 2.56 (s, br,2H); 2.71 (t, br, 2H); 7.55-7.76 (m, 4H); 7.83-7.96 (dd, 2H); 8.59 (dd,1H).

EXAMPLE 1-496-(Hydroxymethyl)-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

269 mg (1.19 mmol) of diisopropylethylamine and, after stirring atnormal temperature for 5 min, sodium borohydride are added under argonto a solution of 500 mg (1.73 mmol) of3,3-dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carboxylic acidand 844 mg (1.91 mmol) ofbenzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate in8.5 ml of tetrahydrofuran. After 80 min, the solvent is removed invacuo, the residue is taken up in diethyl ether, and the organic phaseis washed successively with 1N hydrochloric acid, saturated sodiumbicarbonate solution and saturated brine, dried over magnesium sulfateand concentrated in vacuo. Chromatography on silica gel(cyclohexane/ethyl acetate mobile phase gradient 5:1-2:1) results in 302mg (63%) of the target compound.

MS (ESI+): 275 (M+H);

HPLC: R_(t)=4.47 min;

¹H-NMR (300 MHz, CDCl₃): δ=1.04 (s, 6H); 1.63 (t, 2H); 1.94 (s, br, 1H);2.47 (s, br, 2H); 2.72 (t, 2H); 7.41 (d, br, 1H); 7.53 (s, br, 1H); 8.46(d, 1H).

EXAMPLE 1-506-(Chloromethyl)-3,3-dimethyl-1,2,3,4tetrahydro-9H-thioxanthen-9-one

1.00 g (3.64 mmol) of6-(hydroxymethyl)-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-oneand 1.91 g (7.29 mmol) of triphenylphosphine are introduced into 7.2 mlof dichloromethane, and the mixture is cooled in a dry ice/acetone bathto minus 10° C. Then 1.12 g (7.29 mmol) of tetrachloromethane are addedto the colorless suspension which forms, and the reaction is left tostir overnight while thawing. It is diluted with dichloromethane, washedwith saturated sodium bicarbonate solution, water and with saturatedbrine and dried over magnesium sulfate. The solvent is removed in vacuo,and the residue is adsorbed onto silica gel and filtered through silicagel (mobile phase:cyclohexane/ethyl acetate 5:1). 1.02 g (95%) of thetarget compound are obtained in this way.

MS (ESI+): 293 (M+H);

HPLC: R_(t)=5.35 min;

¹H-NMR (300 MHz, CDCl₃): δ=0.99 (s, 6H); 1.63 (t, 2H); 2.48 (s, 2H);2.72 (t, 2H); 4.64 (s, 2H); 7.47 (dd, 1H); 7.53 (s, br, 1H); 8.49 (d,1H).

EXAMPLE 1-512-(3,3-Dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N-isobutyl-N-methylacetamide

26 mg (0.18 mmol) of 1-hydroxy-1H-benzotriazole hydrate and then 36 mg(0.18 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride are added to a solution of 50 mg (0.17 mmol) of(3,3-dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)acetic acidand 43 mg (0.33 mmol) of dilsopropylethylamine while cooling in ice. Thereaction is left to stir for 15 min and then 16 mg (0.18 mmol) ofN-isobutyl-N-methylamine are added. The mixture is stirred for 19 hduring which the mixture is allowed to reach normal temperature. Forworking up, the mixture is diluted with dichloromethane, washed withwater and saturated sodium chloride solution and dried over magnesiumsulfate. Removal of the solvent in vacuo and chromatography (preparativeHPLC, acetonitrile/water 30:70-95:5) affords 54 mg (88%) of the targetcompound.

MS (ESI+): 372 (M+H);

HPLC: R_(t)=4.95 min;

¹H-NMR (400 MHz, CDCl₃): δ=0.87, 0.90 (2 d, total 6H); 1.03 (s, 6H);1.62 (t, 2H) 1.96 (mc, 1H), 2.46 (s, 2H), 2.71 (t, 2H); 2.96, 2.97 (2s,total 3H); 3.11, 3.23 (2d, total 2H), 3.79, 3.80 (2s, total 2H);7.30-7.40 (2 dd, total 1H); 7.43, 7.44 (2s total 1H); 8.45, 8.45 (2d,total 1H).

STARTING COMPOUNDS II

HPLC methods:

-   Method A: Eluent: A=0.5% HClO₄ in water, B=acetonitrile; gradient:    0.5 min 98% A, 2% B, 4.5 min 10% A, 90% B, 6.7 min 98% A, 2% B; flow    rate: 0.75 ml/min; column temperature: 30° C.; UV detection: 210 nm;    colum: Kromasil C18 (60*2 mm)-   Method C: Eluent: A=0.1% formic acid in acetonitrile, B=0.1% formic    acid in water; gradient: 0 min 10% A, 90% B, 4.0 min 90% A, 10% B,    6.1 min 10% A, 90% B, 7.50 min 10% A, 90% B; flow rate: 0.5 ml/min    0.00-6.10 min, 0 ml/min 6.10-7.5 min, column temperature: 40° C.; UV    detection: 208-400 nm; column: Symmetry C18 (50*2.1 mm), 3.5 μm-   Method D: Eluent: A=acetonitrile, B=0.3 g of 30% HCl in 11 of water;    gradient: 3 min 90% B, 10% A, flow rate 0.9 ml/min, 6 min 90% A, 10%    B, flow rate 1.2 ml/min, column temperature: 50° C.; column:    Symmetry C18 (150*2.1 mm); for other parameters, see method A

EXAMPLE 11-16-(Benzyloxy)-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

60 mg (0.23 mmol) of3-ethyl-6-hydroxy-1,2,3,4-tetrahydro-9H-thioxanthen-9-one, 39.4 mg (0.23mmol) of benzyl bromide and 35 mg (0.25 mmol) of powdered potassiumcarbonate in 2 ml of acetonitrile are heated to reflux under argon at RTovernight. Concentration is followed by to add dichloromethane, washingwith dilute hydrochloric acid and dilute sodium hydroxide solution, andthe organic phase is dried over magnesium sulfate. Concentration resultsin the crude product as an oil which is freed of solvent residues underhigh vacuum. Trituration with a little isopropanol results in a solidwhich is dried in air; yield 37.3 mg (46%), m.p. 94° C.

MS (ESI): 351 (M+H)⁺.

HPLC: 97.4%, retention time 6.06 min (Method A).

The following were prepared in analogy to the method of Example II-1:

EXAMPLE II-23-Ethyl-6-(2-phenylethoxy)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

Yield: 42%, m.p. 105° C., HPLC: 100%, MS (ESI): 365 (M+H)⁺.

EXAMPLE II-33-{[(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)oxy]methyl}benzonitrile

Yield: 72%, m.p. 158° C., HPLC: 100%, MS (ESI): 375 (M)⁺.

Example II-4a and Example II-4bN-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)acetamide and6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

15 ml of polyphosphoric acid, 1.11 g (6.6 mmol) ofN-(3-mercaptophenyl)acetamide and 1.45 g (7.3 mmol) of ethyl4-ethyl-2-oxocyclohexanecarboxylate are heated at 90° C. under argon for30 minutes. After cooling to room temperature, 100 ml of ice-water areadded, and the mixture is stirred for 30 minutes. Extractive working upwith ethyl acetate and washing of the organic phase with 1 N sodiumhydroxide solution and saturated brine affords, after drying over sodiumsulfate and concentration, a crude product which is purified byseparation by column chromatography (silica gel, cyclohexane/ethylacetate mixtures). 135 mg (7%) ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)acetamide areobtained as a solid, m.p. 243° C.

HPLC: 99%, retention time 4.61 min (Method A),

MS (ESI): 302 (M+H)⁺.

As a further fraction, 77 mg (4.5%) of6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one are obtained asa colorless solid, m.p. 187° C.

HPLC: 100%, retention time 4.51 min (Method A),

MS (ESI): 260 (M+H)⁺.

The following were prepared in analogy to the method of Examples II-4aand II-4b:

EXAMPLE II-56-Amino-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

The title compound is obtained from 3-aminothiophenol and ethyl4,4-dimethyl-2-oxocyclohexane carboxylate in polyphosphoric acid (43%).

m.p. 210° C.

HPLC: 100%, retention time 4.44 min (Method A),

MS (EI pos): 259 (M)⁺.

EXAMPLE II-6N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)benzenesulfonaimide

The title compound is obtained in analogy to Example 2-11 frombenzenesulfonyl chloride and6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one.

Yield: 76% colorless crystals.

m.p. 264° C.

HPLC: 100%, retention time 5.20 min (Method A),

MS (ESI): 400 (M+H)⁺.

EXEMPLARY EMBODIMENTS 2 EXAMPLE 2-12-{4-[(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-H-thioxanthen-6-yl)oxy]butyl}-1,2-benzisothiazol-3(2H)-one1,1-dioxide

Under argon, 60 mg (0.23 mmol) of3-ethyl-6-hydroxy-1,2,3,4-tetrahydro-9H-thioxanthen-9-one are dissolvedin 1 ml of tetrahydrofuran and, after addition of 0.34 ml of a 1Msolution of potassium tertiary butoxide in tetrahydrofuran, shaken atroom temperature for 30 min. 110 mg (0.35 mmol) of2-(4-bromobutyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide are added; thesolution is shaken at 65° C. overnight.

After cooling to room temperature, about 130 mg of PS-thiophenol (fromArgonaut, 1.4 mmol/g) are added, and shaken at room temperature for 30min. The solution is filtered, the solid is washed with 0.5 ml ofdimethylformamide, and the filtrate is concentrated under high vacuum.

Purification takes place by preparative HPLC (reverse phase,acetonitrile/water mixtures).

Yield: 22.4 mg (20%).

MS (ESI+): 498 (M+H)⁺.

The compounds listed in the following table are obtained in the sameway: HPLC Method C, Mass (ESI+) retention time Ex. No. Structure [M +H]⁺ in min 2-2

498 5.22 2-3

532 5.47 2-4

512 5.41 2-5

456 5.17 2-6

456 4.76 2-7

462 5.20 2-8

415 4.13

EXAMPLE 2-9(3-Ethyl-9-oxo-2,3,4,5-tetrahydro-1H-thioxanthen-6-yl)2-(1-naphthyl)ethane-sulfonate

31 mg (0.1 mmol) of tetrabutylammmonium bromide and 86 mg of 45% aqueoussodium hydroxide solution are added to a solution of 50 mg (0.19 mmol).of 3-ethyl-6-hydroxy-1,2,3,4-tetrahydro-9H-thioxanthen-9-one in 1 ml ofdichloromethane. After stirring at room temperature for 10 minutes, 59mg (0.23 mmol) of 2-naphthylethanesulfonyl chloride are added. Stirringat room temperature for 1.5 hours is followed by dilution withdichloromethane, and the organic phase is washed with water. Filtrationthrough silica gel, concentration and chromatography of the crudeproduct (silica gel, toluene/ethyl acetate 10/1) affords the titlecompound (37%)

HPLC: 97%, retention time 5.92 min (Method A),

MS (ES): 479 (M+H)⁺.

The following are obtained in analogy to the method of

EXAMPLE 2-9: EXAMPLE 2-103-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl dimethylsulfamate

From dimethylamidosulfonyl chloride; yield: 57%

HPLC: 100%, retention time 5.23 min (Method A),

MS (ESI): 368 (M+H)⁺.

EXAMPLE 2-11N-(3,3-Dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)methanesulfonamide

0.12 ml of pyridine and 0.03 ml (0.35 mmol) of methanesulfonyl chlorideare added to a solution of 75 mg (0.3 mmol) of6-amino-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 4 mg of4-dimethylaminopyridine in 1.5 ml of dichloromethane at 0° C. Stirringat room temperature for 3 h is followed by dilution with dichloromethaneand aqueous working up (1N hydrochloric acid, water, saturated brine).The organic phase is dried over sodium sulfate and then concentrated.The remaining solid is recrystallized from ethyl acetate. The crystalsare washed with a little pentane and dried in vacuo.

Yield: 28 mg (29%) of colorless crystals.

m.p. 272° C.

HPLC: 100%, retention time 4.61 min (Method A),

MS (ESI): 338 (M+H)⁺.

The following are obtained in analogy to the method of Example 2-11:

EXAMPLE 2-12N-(3,3-Dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)benzenesulfonamide

From benzene sulfonyl chloride; yield: 73% colorless crystals.

m.p. 231° C.

HPLC: 100%, retention time 5.01 min (Method A),

MS (ESD: 400 (M+H)⁺.

EXAMPLE 2-13N-(3,3-Dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-4-methylbenzenesulfonamide

From 4-methylbenzenesulfonyl chloride; yield: 60% colorless crystals.

m.p. 279° C.

HPLC: 100%, retention time 5.18 min (Method A),

MS (ESD: 414 (M+H)⁺.

EXAMPLE 2-14 3,3-Dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl[2-(trifluoromethoxy)-phenyl]methanesulfonate

From 2-(trifluoromethoxy)phenyl]methanesulfonyl chloride; yield: 55%colorless crystals.

m.p. 249° C.

HPLC: 100%, retention time 5.32 min (Method A),

MS (ESI): 498 (M+H)⁺.

EXAMPLE 2-15N-(3,3-Dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)isopropylsulfonamide

From isopropylsulfonyl chloride (triple amount); yield: 14% colorlesscrystals.

m.p. 263° C.

HPLC: 100%, retention time 4.85 min (Method A),

MS (ESI): 366 (M+H)⁺.

EXAMPLE 2-16N-(3,3-Dimethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-N-methylbenzenesulfonamide

7.4 ml of 40% sodium hydride in paraffin oil are added to a solution of41 mg (0.1 mmol) ofN-(3,3-dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)benzenesulfonamidein 1 ml of tetrahydrofuran, and the mixture is stirred under argon atroom temperature for 1 hour. 16 mg (0.11 mmol) of methyl iodide areadded. The mixture is stirred at 60° C. overnight. The same amount ofmethyl iodide is then added once again. A further 5 hours at 60° C. arefollowed by aqueous working up (ethyl acetate, water, sat. brine, dryingover sodium sulfate). The crude product is purified by chromatography(silica gel, toluene/ethyl acetate 15:1).

Yield: 24 mg (53%).

HPLC: 92%, retention time 5.28 min (Method A),

MS (ESI): 414 (M+H)⁺.

EXAMPLE 2-17N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N-methylbenzenesulfonamide

A solution of 41 mg (0.1 mmol) ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)benzenesulfonamidein 2 ml of dimethylformamide is mixed with 22 mg of methyl iodide, 3 mgof tetrabutylammmonium bisulfate and 1 g of potassium carbonate andstirred at room temperature for 3 days. Aqueous working up (ethylacetate, water, sat. brine, drying over sodium sulfate) affords a crudeproduct which is purified by chromatography (silica gel, toluene/ethylacetate 10:1). Yield: 27 mg (64%).

HPLC: 98%, retention time 5.44 min (Method A),

MS (DCI NH3): 414 (M+H)⁺.

EXAMPLE 2-18N-(Cyclopropylmethyl)-N-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-benzenesulfonamide

126 mg of 60% sodium hydride are freed of mineral oil with pentane underargon. The washed sodium hydride is mixed with 7 ml of dimethylformamideand then 1.05 gN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)benzenesulfonamideare added. The mixture is stirred at room temperature overnight. Thesolution is made up to a total volume of 10.5 ml with dimethylformamide.

0.5 ml of the above solution (=0.125 mmol of sodium salt of thesulfonamide) is mixed with a solution of 25 mg (0.19 mmol) ofcyclopropylmethyl bromide in 0.5 ml of dimethylformamide and shaken at80° C. overnight. Cooling is followed by addition of 130 mg ofPS-thiophenol (from Argonaut, 1.41 mmol/g) and shaking at roomtemperature for 1 h. Washing with dimethylformamide and concentration ofthe filtrate under high vacuum affords a crude product which is purifiedby HPLC (reverse phase, acetonitrile/water).

Yield: 7 mg (13%).

HPLC: 98%, retention time 3.78 min (Method D),

MS (ESI): 454 (M+H)⁺.

The following are obtained in analogy to the method of Example 2-18:

EXAMPLE 2-19N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N-(2-methoxyethyl)benzenesulfonamide

From 2-methoxyethyl bromide; yield: 41%.

HPLC: 94%, retention time 3.54 min (Method D),

MS (ESI): 458 (M+H)⁺.

EXAMPLE 2-20N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N-(phenylsulfonyl)glycinemethyl ester

From methyl bromoacetate; yield: 54%

HPLC: 100%, retention time 3.43 min (Method D),

MS (ESI): 472 (M+H)⁺.

EXAMPLE 2-21N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N-(2-phenylethyl)benzenesulfonamide

From 2-phenylethyl bromide; yield: 20%

HPLC: 97%, retention time 3.94 min (Method D),

MS (ESI): 504 (M+H)⁺.

EXAMPLE 2-22N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N-propylbenzenesulfonamide

From 1-propyl bromide; yield: 22%

HPLC: 99%, retention time 3.81 min (Method D),

MS (ESI): 442 (M+H)⁺.

EXAMPLE 2-23N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N-ethylbenzenesulfonamide

From ethyl bromide; yield: 14%

HPLC: 96%, retention time 3.67 min (Method D),

MS (ESI): 428 (M+H)⁺.

EXAMPLE 2-243,3-Dimethyl-6-(1H-pyrrol-1-yl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

A solution of 136 mg (0.53 mmol) of6-amino-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one in 1.5 mlof glacial acetic acid is mixed with 83 mg (0.63 mmol) of2,5-dimethoxytetrahydrofuran and heated at 120° C. Thin-layerchromatography shows no precursor detectable after a short time. Thereaction mixture is cooled to room temperature, diluted with ethylacetate and subjected to aqueous working up (water, sodium bicarbonate,water, saturated brine). The crude product obtained after drying andconcentration is purified by column chromatography (silica gel,cyclohexane/ethyl acetate mixtures). The resulting solid is digestedwith cyclohexane. Yield: 69 mg (42%) colorless crystals.

m.p. 169° C.

HPLC: 100%, retention time 5.34 min (Method A),

MS (DCI, NH₃): 310 (M+H)⁺.

The following is obtained in analogy to the method of Example 2-24

EXAMPLE 2-253-Ethyl-6-(1H-pyrrol-1-yl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

From 6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one; yield: 28%colorless crystals.

m.p. 145° C.

HPLC: 99%, retention time 5.49 min (Method A),

MS (DCI, NH₃): 310 (M+H)⁺.

EXEMPLARY EMBODIMENTS 3

The retention time of the prepared examples was determined by HPLC underthe following conditions.

Column: Chromasil C18 60*2; volume injected 1.00 μl; flow rate: 0.75ml/min; eluent: A=5 ml HClO₄/l H₂O, B=CH₃CN; gradient [t(min): A/B]:0.5: 98/2; 4.5: 10/90; 6.5: 10/90; 6.7: 98/2; 7.5: 98:2.

LC-MS Method 1: Method: MHZ 2Q Version No.: 3 MS apparatus type:Micromass Quattro LCZ Ionization: ESI positive/negative HPLC apparatustype: HP 1100 UV detector DAD: 208-400 nm Oven temp.: 40° C. Column:Symmetry C 18 50 mm × 2.1 mm 3.5 μm Supplied by: Waters Gradient: TimeA: % B: % C: % D: % Flow 0.00 10.0 90.0 — — 0.50 4.00 90.0 10.0 — — 0.506.00 90.0 10.0 — — 0.50 6.10 10.0 90.0 — — 1.00 7.50 10.0 90.0 — — 0.50A: CH3CN + 0.1% formic acidB: H2O + 0.1% formic acidC: —D: —

LC-MS Method 2: Method: MHZ 2P Version No.: 3 MS apparatus type:Micromass Platform LCZ Ionization: ESI positive/negative HPLC apparatustype: HP 1100 UV detector DAD: 208-400 nm Oven temp.: 40° C. Column:Symmetry C 18 50 mm × 2.1 mm 3.5 μm Supplied by: Waters Gradient: TimeA: % B: % C: % D: % Flow 0.00 10.0 90.0 — — 0.50 4.00 90.0 10.0 — — 0.506.00 90.0 10.0 — — 0.50 6.10 10.0 90.0 — — 1.00 7.50 10.0 90.0 — — 0.50A: CH3CN + 0.1% formic acidB: H2O + 0.1% formic acidC: —D: —

LC-MS Method 3

Column: Symmetry C18 150*2.1; volume injected 2.00 μl; eluent: A=CH₃CN,B=0.3 g HCl (30%)/l H₂O; gradient [t(min): A/B]: 0: 10/90 flow rate: 0.9m/min; 3.0: 90/10 flow rate: 1.2 ml/min; 6.0: 90/10; flow rate: 1.2ml/min.

EXAMPLE 3-13-Ethyl-N-(2-methylbutyl)-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carboxamide

0.70 g (2.43 mmol) of3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carboxylic acid and3.22 g (7.28 mmol) of 1-benzotriazolyloxytris(dimethylamino)-phosphoniumhexafluorophosphate in 44 ml of THF are stirred at 25° C. under argonfor 15 min. Firstly 0.85 ml (6.07 mmol) of triethylamine and, after afirther 15 min, 1.73 ml (14.6 mmol) of 2-methylbutylamine are addeddropwise to the solution, which is then stirred at 25° C. for 24 h.Dilution with dichloromethane is followed by addition of citric acid (5%strength in water). The phases are separated and the organic phase iswashed with aqueous sodium bicarbonate solution. After the combinedorganic phases have been dried over sodium sulfate and filtered, thesolvent is distilled out under reduced pressure. The residue isprepurified by chromatography on silica gel (0.04-0.063 mm) withdichloromethane/methanol 20:1 as mobile phase. Pure carboxamide issubsequently obtained by a second chromatography on silica gel(0.04-0.063 mm) with cyclohexane/ethyl acetate 2:1 as mobile phase.

Yield: 655 mg (75.5%).

R_(f) (CH₂Cl₂/MeOH 20/1)=0.52.

MS (DCI): 358 (M+H).

HPLC, retention time=5.23 min.

¹H-NMR (200 MHz, CDCl₃): δ=0.96 (t, 3H), 0.99 (d, 3H), 1.00 (t, 3H),1.13-1.53 (m, 5H), 1.63-1.80 (m, 2H), 1.97-2.14 (m, 1H), 2.34-2.63 (m,2H), 2.67-2.83 (m, 1H), 2.84-3.02 (m, 1H), 3.23-3.52 (m, 2H), 6.14-6.28(m, 1H), 7.70 (dd, 1H), 8.00 (d, 1H), 8.54 (d, 1H).

The carboxamides in Table 1 were obtained by the process described forExample 3-1. TABLE 1 Retention Mass Ex. No. Structure Yield time (min)(M + H)⁺ 3-2

90.3% 5.1  344 3-3

59.1% 4.46 (LC-MS Method 2) 330 3-4

83.9% 4.86 344 3-5

76.9% 5.12 370

EXAMPLE 3-86-(1-Azepanylcarbonyl)-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

50.0 mg (0.17 mmol) of3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carboxylic acid, 246mg (0.23 mmol) of PS-carbodiumide (0.94 mmol/g) and 26.6 mg (0.20 mmol)of 1-hydroxy-1H-benzotriazole are shaken in 3 ml of dichloromethane at25° C. under argon for 30 min. Then 13 μl (0.12 mmol) of azepane areadded and the resulting suspension is shaken at 25° C. for 24 h. 165 mg(0.57 mmol) of PS-trisamine (3.5 mmol/g) are added, and shaking iscontinued for 8 h. After filtration, the organic phase is mixed withsodium carbonate solution and filtered through an Extrelut NT1cartridge. The crude product is purified by chromatography on silica gel(0.04-0.063 nm) with cyclohexane/ethyl acetate 3:1 as mobile phase.

Yield: 41.6 mg (97.4%).

R_(f) (cyclohexane/ethyl acetate 3:1)=0.77.

MS (EI): 370 (M+H).

HPLC, retention time=4.98 min.

¹H-NMR (200 MHz, CDCl₃): δ=0.99 (t, 3H), 1.20-1.75 (m, 11H), 1.79-1.94(m, 1 H), 1.97-2.12 (m, 1H), 2.33-2.64 (m, 2H), 2.65-2.81 (m, 1H),2.84-3.02 (m, 1H), 3.26-3.40 (m, 2H), 3.70 (dd, 2H), 7.43 (dd, 1H), 7.52(d, 1H), 8.52 (d, 1H).

EXAMPLE 3-93-Ethyl-N-isopropyl-N-methyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carboxamide

50.0 mg (0.17 mmol) of3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carboxylic acid, 246mg (0.23 mmol) of PS-carbodiimide (0.94 mmol/g) and 26.6 mg (0.20 mmol)of 1-hydroxy-1H-benzotriazole are shaken in 2 ml of dichloromethane at25° C. under argon for 10 min. After addition of 12 μl (0.12 mmol) ofN-isopropyl-N-methylamine, the resulting suspension is shaken at 25° C.for 24 h. 165 mg (0.57 mmol) of PS-trisamine (3.5 mmol/g) are added, andshaking is continued for 16 h. After filtration, the organic phase ismixed with aqueous sodium carbonate solution and filtered through anExtrelut NT1 cartridge. Removal of the solvent by distillation underreduced pressure and chromatography of the residue on silica gel(0.04-0.063 mm) with cyclohexane/ethyl acetate 2:1 as mobile phaseaffords the desired product.

Yield: 19.3 mg (48.6%).

MS (EI): 344 (M+H).

HPLC, retention time=4.76 min.

¹H-NMR (200 MHz, CDCl₃): δ=0.99 (t, 3H), 1.16, (d, 3H), 1.24 (d, 3H),1.33-1.52 (m, 3H), 1.61-1.83 (m, 1H), 1.96-2.13 (m, 1H), 2.33-2.64 (m,2H), 2.65-3.02 (m, 5H), 3.77-3.97 and 4.86-5.08 (m, 1H), 7.42 (br. d,1H), 7.52 (br. s, 1H), 8.52 (d, 1H).

The carboxamides in Table 2 were obtained by the process described forExample 3-8 and 3-9. TABLE 2 Retention Mass Ex. No. Structure Yield time(min) (M + H)⁺ 3-10

35.1% 5.46 372 3-11

51.5% 5.18 358 3-12

45.2% 5.08 356 3-13

96.5% 5.08 (LC-MS Method 1) 384 3-14

99.3% 3.14 (LC-MS Method 3) 342 3-15

86.2% 2.99 (LC-MS Method 3) 328 3-16

38.7% 3.66 (LC-MS Method 3) 384 3-17

45.5% 5.51 (LC-MS Method 2) 400 3-18

70.9% 2.89 (LC-MS Method 3) 358 3-19

51.1% 5.25 358 3-20

59.6% 2.95 (LC-MS Method 3) 316

EXAMPLE 3-213-Ethyl-6-[(2-methoxyethyl)(methyl)amino]-1,2,3,4-tetrahydro-9H-thio-xanthen-9-one

28.9 mg (0.03 mmol) of tris(dibenzylideneacetone)dipalladium, 58.9 mg(0.09 mmol) of (+/−)-2,2-bis(diphenylphosphino)-1,1-binaphthyl and 425mg (4.42 mmol) of sodium tert-butoxide are added to 1020 mg (3.16 mmol)of 6-bromo-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one in aflame-dried flask. The flask is evacuated and then flushed with argonfor 10 min. 0.38 ml (3.79 mmol) of N-(2-methoxyethyl)methylamine and 5ml of toluene are added, and the resulting suspension is stirred at 80°C. for 3 h. The reaction mixture is purified by chromatography on silicagel (0.04-0.063 mm) with cyclohexane/ethyl acetate 5:1/4:1/3:1/2:1 asmobile phase.

Yield: 477 mg (45.6%).

R_(f)(cyclohexane/ethyl acetate 3:1)=0.13.

MS (EI): 332 (M+H).

HPLC, retention time=5.05 min.

¹H-NMR (200 MHz, CDCl₃): δ=0.98 (t, 3H), 1.26-1.49 (m, 3H), 1.59-1.79(m, 1H), 1.93-2.09 (m, 1H), 2.24-2.55 (m, 2H), 2.56-2.72 (m, 1H),2.81-2.98 (m, 1H), 3.08 (s, 3H), 3.36 (s, 3H), 3.56-3.62 (m, 4H), 6.57(d, 1H), 6.85 (dd, 1H), 8.31 (d, 1H).

EXAMPLE 3-223-Ethyl-6-(1-piperidinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

28.3 mg (0.03 mmol) of tris(dibenzylideneacetone)dipalladium, 58.9 mg(0.09 mmol) of (+/−)-2,2-bis(diphenylphosphino)-1,1-binaphthyl and 416mg (4.33 mmol) of sodium tert-butoxide are added to 1000 mg (3.09 mmol)of 6-bromo-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one in aflame-dried flask. The flask is evacuated and then flushed with argonfor 10 min. 0.37 ml (3.71 mmol) of piperidine and 20 ml of toluene areadded, and the resulting suspension is stirred at 80° C. for 3 h.Dilution with 10 ml of diethyl ether, filtration, removal of the solventand subsequent recrystallization of the residue from tert-butyl methylether affords some of the desired product. The major fraction isobtained by chromatography of the filtrate from the recrystallization onsilica gel (0.04-0.063 mm) with cyclohexane/ethyl acetate 7:1/5:1 asmobile phase.

Yield: 719 mg (69.6%)

R_(f) (cyclohexane/ethyl acetate 3:1)=0.40.

MS (DCI): 328 (M+H).

HPLC, retention time=5.43 min.

¹H-NMR (200 MHz, CDCl₃): δ=0.98 (t, 3H), 1.22-1.49 (m, 3H), 1.59-1.79(m, 7H), 1.83-2.09 (m, 1H), 2.25-2.55 (m, 2H), 2.56-2.73 (m, 1H),2.81-2.9 (m, 1H), 3.26-3.43 (m, 4H), 6.75 (d, 1H), 7.02 (dd, 1H), 8.32(d, 1H).

EXAMPLE 3-233-Ethyl-7-fluoro-6-(1-piperidinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

309.9 mg (0.54 mmol) of tris(dibenzylideneacetone)dipalladium, 321.7 mg(0.09 mmol) of 2-(di-t-butylphosphino)biphenyl and 777.1 mg (8.09 mmol)of sodium tert-butoxide are added to 1600 mg (5.39 mmol) of6-chloro-3-ethyl-7-fluoro-1,2,3,4-tetrahydro-9H-thioxanthen-9-one in aflame-dried flask. The flask is evacuated and then flushed with argonfor 10 min. 0.37 ml (3.71 mmol) of piperidine and 10 ml of toluene(degassed) are added, and the resulting suspension is stirred at 100° C.for 16 h. Since reaction was still incomplete, a further 30.9 mg ofcatalyst, 32.1 mg of ligand, 77.7 mg of base and 0.04 ml of piperidineare added, and the mixture is stirred at 100° C. for 24 h. The reactionmixture is mixed with 3 ml of ethyl acetate, filtered through anExtrelut cartridge and then freed of solvent. The residue is purified bychromatography on silica gel (0.04-0.063 mm) with cyclohexane/ethylacetate 15:1/10:1 as mobile phase.

Yield: 545 mg (29.2%).

R_(f) (cyclohexane/diethyl ether 10:1)=0.17.

MS (EI): 346 (M+H).

HPLC, retention time=5.80 min.

¹H-NMR (200 MHz, CDCl₃): δ=0.95 (t, 3H), 1.29-1.50 (m, 3H), 1.57-1.83(m, 7H), 1.85-2.10 (m, 1H), 2.29-2.59 (m, 2H), 2.60-2.75 (m, 1H),2.81-2.98 (m, 1H), 3.18 (dd, 4H), 6.87 (d, 1H), 8.07 (d, 1H).

EXAMPLE 3-246-(1,5-Dioxa-9-azaspiro[5.5]undec-9-yl)-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

2.8 mg (0.003 mmol) of tris(dibenzylideneacetone)dipalladium, 5.9 mg(0.009 mmol) of (+/−)-2,2-bis(diphenylphosphino)-1,1-binaphthyl and 41.6mg (0.43 mmol) of sodium tert-butoxide are added to 100 mg (0.31 mmol)of 6-bromo-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one in aflame-dried flask. The flask is evacuated and then flushed with argonfor 10 min. 59.6 mg (0.37 mmol) of 1,5-dioxa-9-azaspiro[5.5]undecane and1 ml of toluene are added, and the resulting suspension is stirred at80° C. for 5 h. Purification of the reaction mixture by chromatographyon silica gel (0.04-0.063 mm) with cyclohexane/ethyl acetate 5:1/3:1/1:1as mobile phase affords the required product.

Yield: 83 mg (67.5%).

R_(f) (cyclohexane/ethyl acetate 1:1)=0.38.

MS (LC-MS): 400 (M+H).

HPLC, retention time=5.03 min (LC-MS Method 1).

¹H-NMR (200 MHz, CDCl₃): δ=0.98 (t, 3H), 1.27-1.49 (m, 3H), 1.64-1.84(m, 3H), 1.93-2.07 (m, 5H), 2.26-2.57 (m, 2H), 2.58-2.73 (m, 1H),2.81-2.98 (m, 1H), 3.43 (dd, 4H), 3.95 (dd, 4H), 6.77 (d, 1H), 7.03 (dd,1H), 8.33 (d, 1H).

The compounds in Table 3 were obtained by the processes described forExamples 3-21 to 3-24. TABLE 3 Retention Mass Ex. No. Structure Yieldtime (min) (M + H)⁺ 3-25

18.8% 5.4  314 3-26

29.6% 5.06 330 3-27

39.6% 4.22 357 3-28

18.7% 5.73 356 3-29

21.8% 5.55 429 3-30

29.5% 6.05 (LC-MS Method 1) 356 3-31

88.9% 5.29 300 3-32

48.1% 4.28 357 3-33

22.3% 6.51 356 3-34

70.5% 4.78 343 3-35

18.3% 5.68 (LC-MS Method 2) 330 3-36

31.6% 5.42 (LC-MS Method 2) 328 3-37

58.5% 5.35 287 3-38

20.5% 6.17 329 3-39

9.4% 5.41 (LC-MS Method 2) 316

EXAMPLE 3-401-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-4-piperidinone

At 0° C., 0.50 ml of triflouroacetic acid (40% in H₂O) is added dropwiseto a solution of 65 mg (0.16 mmol) of6-(1,5-dioxa-9-azaspiro[5.5]undec-9-yl)-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-onein 5 ml of dichloromethane. The mixture is stirred at 25° C. for 48 hand then 10 ml of sodium hydroxide solution (1 N) are added. Afterextraction of the organic phase with dichloromethane, the combinedorganic phases are dried over sodium sulfate. Filtration, removal of thesolvent under weak vacuum and chromatography of the residue on silicagel (0.04-0.063 mm) with cyclo-hexane/diethyl ether 1:4 as mobile phaseaffords the desired product.

Yield: 27 mg (48.6%).

R_(f) (cyclohexane/diethyl ether 1:5)=0.17.

MS (EI): 342 (M+H).

HPLC, retention time=4.69 min.

¹H-NMR (200 MHz, CDCl₃): δ=0.99 (t, 3H), 1.30-1.51 (m, 3H), 1.59-1.81(m, 1H), 1.95-2.12 (m, 1H), 2.26-2.78 (m, 3H), overlapped by 2.60 (dd,4H), 2.81-2.99 (m, 1H), 3.77 (dd, 4H), 6.81 (d, 1H), 7.05 (dd, 1H), 8.39(d, 1H).

EXAMPLE 3-413-Ethyl-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

2.9 mg (0.005 mmol) of tris(dibenzylideneacetone)dipalladium, 3.1 mg(0.01 mmol) of 2-(di-t-butylphosphino)biphenyl and 17.3 mg (0.18 mmol)of sodium tert-butoxide are added to 41.7 mg (0.13 mmol) of6-bromo-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one in a flame-driedflask. The flask is evacuated and then flushed with argon. 0.02 ml (0.15mmol) of N-methylaniline and 0.3 ml of toluene are added, and theresulting suspension is stirred at 80° C. for 24 h. The reaction mixtureis diluted with 10 ml of ethyl acetate, filtered through Celite and thenpurified by preparative HPLC (RP-C18, acetonitrile/H₂O gradient).

Yield: 32.1 mg (71.2%).

R_(f) (cyclohexane/ethyl acetate 5:1)=0.28.

MS (EI): 350 (M+H).

HPLC, retention time=5.89 min.

¹H-NMR (200 MHz, CDCl₃): δ=0.98 (t, 3H), 1.22-1.49 (m, 3H), 1.59-1.78(m, 1H), 1.93-2.09 (m, 1H), 2.25-2.72 (m, 3H), 2.81-2.98 (m, 1H), 3.38(s, 3H), 6.70 (d, 1H), 6.86 (dd, 1H), 7.18-7.31 (m, 3H), 7.36-7.48 (m,2H), 8.26 (d, 1H).

The compounds in Table 4 were obtained by the process described forExample 3-41. TABLE 4 Retention Mass Ex. No. Structure Yield time (min)(M + H)⁺ 3-42

43.5% 5.61 336 3-43

8.1% 5.00 (LC-MS Method 1) 311

EXAMPLE 3-443-[(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)oxy]-4-methylbenzonitrile

6.8 mg (0.007 mmol) of tris(dibenzylideneacetone)dipalladium, 3.4 mg(0.006 mmol) of 2-(di-t-butylphosphino)biphenyl and 78.8 mg (0.37 mmol)of potassium phosphate are added to 60 mg (0.19 mmol) of6-bromo-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one in a flame-driedflask. The flask is evacuated and then flushed with argon. Afteraddition of 30 mg (0.22 mmol) of 2-hydroxy-4-methylbenzonitrile and 1.0ml of toluene (degassed), the resulting suspension is stirred at 100° C.for 24 h. The reaction mixture is diluted with 3 ml of dichloromethaneand, after addition of 0.5 ml of sodium hydroxide solution (1 N),filtered through an NT1-Extrelut cartridge. Removal of the solvent underreduced pressure and chromatography of the residue on silica gel(0.04-0.063 mm) with cyclohexane/diethyl ether 5:1 as mobile phase leadsto the desired product.

Yield: 29.1 mg (41.8%).

R_(f) (cyclohexane/ethyl acetate 5:1)=0.33.

MS (EI): 376 (M+H).

HPLC, retention time=5.78 min.

¹H-NMR (200 MHz, CDCl₃): δ=0.99 (t, 3H), 1.21-1.50 (m, 3H), 1.60-1.79(m, 1H), 1.96-2.12 (m, 1H), 2.30 (s, 3H), 2.34-2.77 (m, 3H), 2.82-3.00(m, 1H), 6.88 (d, 1H), 7.03 (dd, 1H), 7.20-7.31 (m, 1H, overlapped byCHCl₃ signal), 7.35 (br. d, 1H), 7.46 (dd, 1H), 8.50 (d, 1H).

The compounds in Table 5 were obtained by the process described forExample 3-44. TABLE 5 Retention Mass Ex. No. Structure Yield time (min)(M + H)⁺ 3-45

49.3% 5.74 (LC-MS Method 2) 337 3-46

45.5% 5.76 (LC-MS Method 2) 355 3-47

39.6% 5.86 (LC-MS Method 1) 373 3-48

10.5% 5.58 (LC-MS Method 2) 391

EXAMPLE 3-49N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)propanamide

30 μl (0.30 mmol) of propionyl chloride are added dropwise to asuspension of 70 mg (0.27 mmol) of6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one in 3.5 ml ofdichloromethane. After 10 min, 40 μl (0.30 mmol) of triethylamine areadded, and the mixture is stirred under reflux for 4 h. After cooling,the reaction solution is poured into 10 ml of ice-water and, afterthawing, part of the product is filtered off as solid. The latter ispurified by recrystallization from acetonitrile. The filtrate isneutralized with sat. aqueous sodium carbonate solution. The solidobtained after extraction of the aqueous phase with dichloromethane andremoval of the solvent is recrystallized from acetonitrile.

Yield: 71 mg (78.4%).

R_(f) (cyclohexane/ethyl acetate 1:2=0.58.

MS (EI): 315 (M).

HPLC, retention time=4.89 min.

¹H-NMR (200 MHz, DMSO-d₆): δ=0.94 (t, 3H), 1.09 (t, 3H), 1.21-1.46 (m,3H), 1.51-1.75 (m, 1H), 1.87-2.03 (m, 1H), 2.26-2.47 (m, 4H), 2.62-2.82(m, 2H), 7.53 (dd, 1H), 8.17 (d, 1H), 8.23 (d, 1H), 10.4 (s, 1H).

The compounds in Table 6 were obtained by the process described forExample 3-49. TABLE 6 Retention Mass Ex. No. Structure Yield time (min)(M + H)⁺ 3-50

7.8% 4.4 361 3-51

85.6% 5.09 330 3-52

95.6% 5.3 344 3-53

89.3% 4.72 332

The compounds in Table 7 were obtained by the process described forExample 1-10: TABLE 7 Retention Mass Ex. No. Structure Yield time (min)(M + H)⁺ 3-54

74.1% 5.87 351 3-55

56.3% 4.85 323 3-56

53.9% 5.02 383 3-57

35.3% (by product) 5.19 245 3-58

27.3% 5.63 365 3-59

75.2% 6.49 355 3-60

48.9% 6.2 339 3-61

50.2% 6.19 339 3-62

58.8% 6.28 357 3-63

88.7% 6.08 357 3-64

84.7% 6.01 356 3-65

94.3% 5.99 356 3-66

71.3% 6.62 388 3-67

69.8% 6.05 367 3-68

18.4% 4.34 352

EXAMPLE 3-69N,3,3-Trimethyl-9-oxo-N-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1-thioxanthene-6-carboxamide

0.70 g (2.43 mmol) of3,3-dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carboxylic acidand 3.22 g (7.28 mmol) of1-benzotriazolyloxytris(dimethylamino)-phosphonium hexafluorophosphateare stirred in 14 ml of THF at 25° C. under argon for 15 min. Firstly0.85 ml (6.07 mmol) of triethylamine and, after a further 15 min, 1.10 g(9.71 mmol) of N-(2-trifluoroethyl)methylamine are added dropwise to thesolution, which is then stirred at 25° C. for 24 h. Dilution withdichloromethane is followed by addition of citric acid (5% strength inwater). The phases are separated and the organic phase is washed withaqueous sodium bicarbonate solution. After the combined organic phaseshave been dried over sodium sulfate and filtered, the solvent isdistilled out under reduced pressure. The residue is purified bypreparative

HPLC (RP-C18, acetonitrile/water gradient).

Yield: 838 mg (88.8%).

R_(f) (cyclohexane/ethyl acetate 2/1)=0.20.

MS (DCI): 384 (M+H).

HPLC, retention time=4.86 min.

¹H-NMR (200 MHz, CDCl₃): δ=1.04 (s, 6H), 1.64 (t, 2H), 2.49 (br. s, 2H),2.72 (t, 2H), 3.11 (br. s, 3H), 3.66-4.35 (m, 2H), 7.47 (d 1H), 7.58 (s,1H), 8.56 (d, 1H).

EXAMPLE 3-707-Fluoro-N-isobutyl-N,3,3-trimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carboxamide

0.43 g (1.40 mmol) of5-fluoro-3,3-dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carboxylicacid and 1.86 g (4.21 mmol) of1-benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphateare stirred in 7 ml of THF at 25° C. under argon for 15 min. Firstly0.49 ml (3.51 mmol) of triethylamine and, after a further 15 min, 0.49 g(5.61 mmol) of N-methylisobutylamine are added dropwise to the solution,which is then stirred at 25° C. for 24 h. Dilution with dichloromethaneis followed by addition of citric acid (5% strength in water). Thephases are separated and the organic phase is washed with aqueous sodiumbicarbonate solution. After the combined organic phases have been driedover sodium sulfate and filtered, the solvent is distilled out underreduced pressure. The residue is purified by preparative HPLC (RP-C18,acetonitfile/water gradient).

Yield: 541.4 mg (85.6%).

R_(f) (cyclohexane/ethyl acetate 2/1)=0.45.

MS (EI): 376 (M).

HPLC, retention time=5.17 min.

¹H-NMR (200 MHz, CDCl₃): δ=0.76 (d, 3H), 1.00 (d, 3H), 1.04 (s, 6H),1.64 (t, 2H), 1.84-2.19 (m, 1H), 2.49 (br. s, 2H), 2.72 (t, 2H), 2.89and 3.10 (2s, 3H), 3.00 and 3.41 (2d, 2H), 7.53 (dd, 1H), 8.21 (dd, 1H).

The carboxamides in Table 8 are obtained in analogy to the processesdescribed for Examples 3-1, 3-6, 3-7, 3-69 and 3-70. TABLE 8 RetentionMass Ex. No. Structure Yield time (min) (M + H)⁺ 3-71

64.5% 5.15 357 (M) 3-72

52.9% 2.63 (LC-MS Method 3) 360 3-73

54.7% 4.54 388 3-74

53.7% 4.69 374 3-75

91.6% 4.67 (LC-MS Method 3) 344 3-76

51.3% 5.21 384 3-77

88.1% 4.51 342 3-78

92.8% 4.26 (LC-MS Method 1) 340 3-79

86.6% 4.62 (LC-MS Method 1) 374 3-80

83.9% 4.26 (LC-MS Method 1) 374 3-81

60.5% 4.13 (LC-MS Method 1) 360 3-82

94.5% 4.67 404 3-83

11.1% 4.21 407 3-84

22.8% 4.20 (LC-MS Method 1) 388 3-85

22.5% 4.60 (LC-MS Method 1) 401 (M) 3-86

62.3% 4.95 344 3-87

16.5% 3.12 (LC-MS Method 3) 372

The carboxamides in Table 9 were obtained in analogy to the processesdescribed for Examples 3-8 and 3-9. TABLE 9 Retention Mass Ex. No.Structure Yield time (min) (M + H)⁺ 3-88

44.9% 1.86 (LC-MS Method 3) 359 3-89

13.5% 4.72 (LC-MS Method 2) 384

EXAMPLE 3-90N-Ethyl-N-(2-hydroxy-2-methylpropyl)-3,3-dimnethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxarthene-6-carboxamide

50 μl (0.46 mmol) of N-methylmorpho line, 35 mg (0.23 mmol) ofN-ethylamino-2-methyl-2-propanol hydrochloride and 34 mg (0.25 mmol) of1-hydroxy-1H-benzotriazole hydrate are added to a stirred suspension of60 mg (0.21 mmol) of3,3-dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carboxylic acidin 10 ml of dichloromethane. The mixture is cooled to 0° C., and then 48mg (0.25 mmol) of N-(3-dimethylaminopropyl)-N-ethylcarbodiimdehydrochloride are added. The cooling bath is removed and the mixture isstirred at 25° C. for 24 h. The solvent is distilled out under reducedpressure, and the resulting residue is purified by preparative HPLC(RP-C18, acetonitrile/water gradient). Pure carboxamide is subsequentlyobtained by a second chromatography of the prepurified product obtainedin this way on silica gel (0.04-0.063 mm) (dichloromethane/methanol30:1, 20:1, 10:1, 5:1, 1:1 as mobile phase).

Yield: 33.2 mg (41.2%).

R_(f) (CH₂Cl₂/MeOH 10/1)=0.55.

LC-MS (Method 1): 388 (M+H).

LC-MS, retention time=4.10 min.

¹H-NMR (200 MHz, CDCl₃): δ=1.04 (s, 6H), 1.08 (t, 3H), 1.33 (s, 6H),1.64 (t, 2H), 2.49 (s, 2H), 2.73 (t, 2H), 3.37 (q, 2H), 3.58 (s, 2H),4.06 (s, 1H), 7.47 (dd, 1H), 7.54 (br. s, 1H), 8.55 (d, 1H).

The carboxamides in Table 10 are obtained in analogy to the processdescribed for Example 3-90. TABLE 10 Retention Mass Ex. No. StructureYield time (min) (M + H)⁺ 3-91

77.5% 3.41 (LC-MS Method 2) 393 3-92

70.3% 4.32 419 3-93

83.3 4.23 407

EXAMPLE 3-94N-Ethyl-N-isobutyl-3,3-dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carboxamide

0.127 g (5.03 mmol) of sodium hydride is added to a solution of 0.576 g(1.68 mmol) ofN-isobutyl-3,3-dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carboxamidein 19 ml of THF at 0° C. under argon, and the mixture is stirred at 0°C. for 15 min. Then 0.67 ml (8.4 mmol) of iodoethane is added, and thecooling bath is removed. After stirring at 25° C. for 2 h, 2 ml of waterare cautiously added, and dilution with ethyl acetate is followed byfiltration through an Extrelut NT3 cartridge. The solvent is distilledoff under reduced pressure, and the resulting residue is purified bypreparative HPLC (RP-C 18, acetonitrile/water gradient).

Yield: 275.9 mg (43.6%).

R_(f) (cyclohexane/ethyl acetate 3/1)=0.23.

LC-MS (Method 2): 371 (M+H).

HPLC, retention time=5.00 min.

EXAMPLE 3-95N-(Cyclopropylmethyl)-N-ethyl-3,3-dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carboxamide

32.4 mg (1.28 mmol) of sodium hydride are added to a solution of 146 mg(0.43 mmol) ofN-(cyclopropylmethyl)-3,3-dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthene-6-carboxamidein 2.8 ml of THF at 0° C. under argon, and the mixture is stirred at 0°C. for 15 min. Then 0.17 ml (2.1 mmol) of iodoethane is added, and thecooling bath is removed. After stirring at 25° C. for 1 h, 2 ml of waterare cautiously added, and dilution with ethyl acetate is followed byfiltration through an Extrelut NT3 cartridge. The solvent is distilledout under reduced pressure and the resulting residue is purified bypreparative HPLC (RP-C18, acetonitrile/water gradient).

Yield: 275.9 mg (43.6%).

R_(f) (cyclohexane/ethyl acetate 1/1)=0.55.

LC-MS (Method 3): 370 (M+H).

LC-MS, retention time=3.02 min.

The compounds in Table 11 are obtained in analogy to the processesdescribed for Examples 3-21 to 3-24. TABLE 11 Retention Mass Ex. No.Structure Yield time (min) (M + H)⁺ 3-96

18.1% 6.17 (LC-MS Method 2) 356 3-97

64.6% 5.42 357 3-98

6.2 5.09 (LC-MS Method 2) 356 3-99

28.5 4.82 (LC-MS Method 2) 360 3-100

39.1 3.86 (LC-MS Method 3) 418 3-101

58.9 5.03 332 3-102

14.2 5.29 (LC-MS Method 1) 418

The compounds in Table 12 are obtained from the corresponding ketals inanalogy to the process described for

EXAMPLE 3-40.

TABLE 12 Retention Mass Ex. No. Structure Yield time (min) (M + H)⁺3-103

65.5% 4.79 360 3-104

89.4% 2.75 (LC-MS Method 3) 342 3-105

82.6% 4.69 360

EXAMPLE 3-106N-(3,3-Dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)propanamide

0.55 ml (6.36 mmol) of propionyl chloride is added dropwise to asuspension of 1.50 g (5.78 mmol) of6-amino-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one in 75 ml ofdichloromethane. After 10 min, 0.89 ml (6.36 mmol) of triethylamine isadded, and the mixture stirred under reflux for 1 h. A further 50 μl(0.6 mmol) of propionyl chloride and 80 μl (0.6 mmol) of triethylamineare added and then the mixture is stirred under reflux for 3 h. Aftercooling, the reaction solution is added to 40 ml of ice-water and, afterthawing, part of the product is filtered off as solid. The filtrate istaken up in 30 ml of dichloromethane and added to 20 ml of ice-water.After thawing, further product is filtered off as solid.

Yield: 1.337 g (73.3%).

R_(f) (cyclohexane/ethyl acetate 1:2=0.64.

MS (EI): 316 (M+H).

HPLC, retention time=4.73 min.

¹H-NMR (200 MHz, DMSO-d₆): δ=0.98 (s, 6H), 1.09 (t, 3H), 1.56 (t, 2H),2.39 (q, 2H), 2.46-2.59 (m, 4H), 7.54 (dd, 1H), 8.17 (d, 1H), 8.24 (d,1H), 10.3 (s, 1H).

EXAMPLE 3-107N-(3,3-Dimethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N,N-dimethylglycinamide

0.476 g (4.62 mmol) of N,N-dimethylglycine is added to a solution of1.10 g (4.20 mmol) of6-amino-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 2.39 g(6.30 mmol) of o-(7-azobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate in 11 ml of N,N-dimethylformamide under argon. Themixture is stirred at 60° C. for 9 h. After cooling, the reactionmixture is purified by preparative HPLC (RP-C18, acetonitrile/watergradient).

Yield: 71 mg (92.8%).

R_(f) (dichloromethane/methanol 20:1=0.35.

MS (EI): 345 (M+H).

HPLC, retention time=4.02 min.

¹H-NMR (200 MHz, DMSO-d₆): δ=0.98 (s, 6H), 1.57 (t, 2H), 2.39-2.61 (m,4H), 2.88 (s, 6H), 4.17 (s, 2H), 7.59 (dd, 1H), 8.10 (d, 1H), 8.32 (d,1H), 10.9 (s, 1H).

The compounds in Table 13 are obtained in analogy to the processdescribed for Example 3-107. TABELLE 13 Retention Mass Ex. No. StructureYield time (min) (M + H)⁺ 3-108

42.6% 2.91 (LC-MS Method 2) 345 3-109

8.9% 2.88 (LC-MS Method 2) 331

STARTING COMPOUNDS IV EXAMPLE IV-1N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-1-butanesulfonamide

120 μl (1.45 mmol) of pyridine and a spatula tip of4-dimethylaminopyridine are added to a solution of 75 mg (0.29 mmol) of6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 55 mg (0.35mmol) of butanesulfonyl chloride in 2 ml of methylene chloride. Themixture is stirred at room temperature overnight. The reaction mixtureis then diluted with 30 ml of methylene chloride and subsequently washedwith water, 1N hydrochloric acid and saturated sodium chloride solution.The organic phase is dried over sodium sulfate and concentrated. Theresulting residue is recrystallized from ethyl acetate. 15 mg (0.04mmol, 13% yield) of the product are obtained as a pale yellowmicrocrystalline solid.

R_(f): 0.23 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.45 (d, 1H), 7.40 (d, 1H), 7.14 (dd,1H), 6.69 (s, 1H), 3.16 (m, 2H), 2.91 (m, 1H), 2.61 (dd, 1H), 2.58-2.34(m, 2H), 2.02 (m, 1H), 1.82 (m, 2H), 1.71 (m, 1H), 1.48-1.32 (m, 5H),0.99 (t, 3H), 0.89 (t, 3H).

MS (ESI): 380.2 ([M+H]⁺).

EXAMPLE IV-2N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-3-pyridinesulfonamide

60 mg (0.15 mmol, 51% yield) of the product are obtained as a paleyellow microcrystalline solid from 75 mg (0.29 mmol) of6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 75 mg (0.35mmol) of 3-pyridylsulfonyl chloride in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-1-butanesulfonamide.

R_(f): 0.21 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 401.1 ([M+H]⁺).

EXAMPLE IV-3N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-3-methylbenzenesulfonamide

14 mg (0.03 mmol, 9% yield) of the product are obtained as a colorlessmicrocrystalline solid from 100 mg (0.39 mmol) of6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 87 mg (0.46mmol) of m-tolylsulfonyl chloride in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-1-butanesulfonamide.

R_(f): 0.24 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 414 ([M+H]⁺).

EXAMPLE IV-42-Cyano-N-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-benzenesulfonamide

60 mg (0.14 mmol, 49% yield) of the product are obtained as a paleyellow microcrystalline solid from 75 mg (0.29 mmol) of6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 71 mg (0.35mmol) of 2-cyanophenylsulfonyl chloride in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-1-butanesulfonamide.

R_(f): 0.18 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 425.0 ([M+H]⁺).

EXAMPLE IV-53-Cyano-N-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-benzenesulfonamide

20 mg (0.05 mmol, 16% yield) of the product are obtained as a paleyellow microcrystalline solid from 75 mg (0.29 mmol) of6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 71 mg (0.35mmol) of 3-cyanophenylsulfonyl chloride in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-1-butanesulfonamide.

R_(f): 0.18 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 425.0 ([M+H]⁺).

EXAMPLE IV-64-Cyano-N-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-benzenesulfonamide

140 mg (0.33 mmol, 85% yield) of the product are obtained as a paleyellow microcrystalline solid from 100 mg (0.39 mmol) of6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 93 mg (0.46mmol) of 4-cyanophenylsulfonyl chloride in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-1-butanesulfonamide.

R_(f): 0.18 (Cyclohexane/ethyl acetate 2:1).

MS (ESI): 425.0 ([M+H]⁺).

EXAMPLE IV-7N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-1-propanesulfonamide

25 mg (0.07 mmol, 23% yield) of the product are obtained as a yellowmicrocrystalline solid from 75 mg (0.29 mmol) of6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 50 mg (0.35rnmol) of n-propylsulfonyl chloride in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-1-butanesulfonamide.

R_(f): 0.19 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 10.49 (s, 1H), 8.25 (d, 1H), 7.38 (d,1H), 7.33 (dd, 1H) 3.24 (t, 2H), 2.70 (m, 2H), 2.41 (t, 2H), 2.11 (t,2H), 1.95 (m, 1H), 1.67 (m, 2H), 1.37 (m, 2H), 1.11 (1, 3H), 0.93 (t,3H).

MS (ESI): 366.2 ([M+H]⁺).

EXAMPLE IV-8N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)cyclopropanesulfonamide

71 mg (0.19 mmol, 34% yield) of the product are obtained as a colorlessmicrocrystalline solid from 150 mg (0.58 mmol) of6-amino-3-ethyl-1,2,3,4-tetra-hydro-9H-thioxanthen-9-one and 97 mg (0.69mmol) of cyclopropylsulfonyl chloride in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-1-butanesulfonamide.

R_(f): 0.25 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 364 ([M+H]⁺).

EXAMPLE IV-9N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-4-methoxybenzenesulfonamide

110 mg (0.26 mmol, 66% yield) of the product are obtained as a paleyellow microcrystalline solid from 100 mg (0.39 mmol) of6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 95 mg (0.46mmol) of 4-methoxyphenylsulfonyl chloride in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-1-butanesulfonamide.

R_(f): 0.15 (ethyl acetate/cyclohexane 2:1).

MS (ESI): 430 ([M+H]⁺).

EXAMPLE IV-103-Chloro-N-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)benzenesulfonamide

30 mg (0.07 mmol, 18% yield) of the product are obtained as a colorlessmicrocrystalline solid from 100 mg (0.39 mmol) of6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 89 mg (0.42mmol) of 3-chlorophenylsulfonyl chloride in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-1-butanesulfonamide.

R_(f): 0.33 (ethyl acetate/cyclohexane 2:1).

MS (ESI): 434 ([M+H]⁺).

EXAMPLE IV-11N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-2-methylbenzenesulfonamide

36 mg (0.09 mmol, 23% yield) of the product are obtained as a paleyellow microcrystalline solid from 100 mg (0.39 mmol) of6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 88 mg (0.46mmol) of o-tolylsulfonyl chloride in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-1-butanesulfonamide.

R_(f): 0.16 (ethyl acetate/cyclohexane 2:1).

MS (ESI): 414.1 ([M+H]⁺).

EXAMPLE IV-12N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-2,4-dimethylbenzenesulfonamide

80 mg (0.19 mmol, 48% yield) of the product are obtained as a yellowmicrocrystalline solid from 100 mg (0.39 mmol) of6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 94 mg (0.46mmol) of 2,4-dimethylphenylsulfonyl chloride in analogy to the synthesisofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-1-butanesulfonamide.

R_(f): 0.20 (ethyl acetate/cyclohexane 2:1).

MS (ESI): 428 ([M+H]⁺).

EXAMPLE IV-13N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-3-nitrobenzenesulfonamide

70 mg (0.15 mmol, 27% yield) of the product are obtained as a colorlessmicrocrystalline solid from 150 mg (0.58 mmol) of6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 153 mg (0.69minol) of 3-nitrophenylsulfonyl chloride in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-1-butanesulfonamide.

R_(f): 0.07 (ethyl acetate/cyclohexane 2:1).

MS (ESI): 444.9 ([M+H]⁺).

EXAMPLE IV-145-Chloro-N-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-2-thiophenesulfonamide

105 mg (0.24 mmol, 41% yield) of the product are obtained as a yellowmicrocrystalline solid from 150 mg (0.58 mmol) of6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 150 mg (0.69mmol) of 5-chlorothiophenesulfonyl chloride in analogy to the synthesisofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-1-butanesulfonamide.

R_(f): 0.33 (ethyl acetate/cyclohexane 2:1).

MS (ESI): 440 ([M+H]⁺).

EXAMPLE IV-15N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-2-naphthalenesulfonamide

73 mg (0.16 mmol, 28% yield) of the product are obtained as a yellowmicrocrystalline solid from 150 mg (0.58 mmol) of6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 156 mg (0.69mmol) of 2-naphthalenesulfonyl chloride in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-1-butanesulfonamide

R_(f): 0.41 (ethyl acetate/cyclohexane 2:1).

MS (ESI): 450 ([M+H]⁺).

EXAMPLE IV-16N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-2-thiophenesulfonamide

123 mg (0.30 mmol, 52% yield) of the product are obtained as a paleyellow solid from 150 mg (0.58 mmol) of6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 126 mg (0.69mmol) of 2-thiophenesulfonyl chloride in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-1-butanesulfonamide.

R_(f): 0.36 (ethyl acetate/cyclohexane 2:1).

MS (ESI): 406 ([M+H]⁺).

EXAMPLE IV-172-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)ethanesulfonamide

125 mg (0.25 mmol, 42% yield) of the product are obtained as a paleyellow solid from 150 mg (0.58 mmol) of6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 188 mg (0.69mmol) of 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethanesulfonylchloride in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-1-butanesulfonamide.

R_(f): 0.32 (ethyl acetate/cyclohexane 2:1).

MS (ESI): 497.1 ([M+H]⁺).

EXEMPLARY EMBODIMENTS 4 EXAMPLE 4-16-Amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

426 g of polyphosphoric acid are stirred at room temperature under argonfor 15 minutes. They are then heated at about 150° C. for 5 minutes andallowed to cool, and 15.0 g (120 mmol) of 3-aminothiophenol and 21.6 g(109 mmol) of ethyl 4-ethyl-2-oxocyclohexanecarboxylate are cautiouslyadded. The mixture is stirred at 90° C. for 2 hours and allowed to coolto room temperature. 430 ml of ice-water are added to the resulting redmixture and, after stirning for 30 minutes, it is extracted ten timeswith ethyl acetate. The combined organic phases are washed successivelywith water, saturated sodium bicarbonate solution, water and saturatedsodium chloride solution and dried over sodium sulfate. After removal ofthe solvent, the crude product is mixed with methylene chloride,whereupon part of the product (5.46 g) precipitates as a yellow solid.The filtrate is purified by column chromatography (silica gelcyclohexane/ethyl acetate 40:1). The product fraction (6.18 g) isconcentrated and dried in vacuo. A total of 11.64 g (44.9 mmol, 41%yield) of a yellow solid is obtained.

R_(f): 0.17 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 7.98 (d, 1H), 6.72 (dd, 1H), 6.60 (d,1H), 6.12 (s, 2H), 2.66 (m, 2H), 2.32 (m, 2H), 1.91 (m, 1H), 1.62 (m,1H), 1.34 (m, 3H), 0.93 (t, 3H).

MS (EI): 259 (M⁺).

EXAMPLE 4-23-Ethyl-6-(ethylamino)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

2.19 mg (57.8 mmol) of sodium borohydride are added to a solution of 1.5g (5.8 mmol) of 6-amino-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-onein 40 ml of glacial acetic acid, and the mixture is stirred at roomtemperature for 2 hours. The solution is then diluted with 200 ml ofwater, and 2N sodium hydroxide solution is added until the pH is 9.Extraction with methylene chloride and drying on sodium sulfate arefollowed by evaporation to dryness. The crude product is purified bycolumn chromatography (silica gel, methylene chloride/methanol600:1-100:1). The product fraction is concentrated and dried in vacuo.1.01 g (3.51 mmol, 60% yield) of a pale yellow solid are obtained.6-(Diethylamino)-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one isobtained as byproduct.

R_(f): 0.74 (methylene chloride/methanol 20:1).

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 7.99 (d, 1H), 6.76 (dd, 1H), 6.65 (t,1H), 6.56 (d, 1H), 3.12 (dq, 2H), 2.67 (m, 2H), 2.34 (m, 2H), 1.92 (m,1H), 1.60 (m, 1H), 1.32 (m, 3H), 1.18 (t, 3H), 0.94 (t, 3H).

MS (EI: 287 (M⁺).

EXAMPLE 4-36-(Diethylamino)-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

6-(Diethylamino)-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one isobtained as byproduct in the synthesis of3-ethyl-6-(ethylamino)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one. 373 mg(1.18 mmol, 20% yield) of a pale yellow solid are isolated.

R_(f): 0.37 (cyclohexane/ethyl acetate 20:1).

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 8.07 (d, 1H), 6.89 (dd, 1H), 6.68 (d,1H), 3.42 (q, 4H), 2.67 (m, 2H), 2.34 (m, 2H), 1.92 (m, 1H), 1.60 (m,1H), 1.32 (m, 3H), 1.12 (t, 6H), 0.94 (t, 3H).

MS (EI): 315 (M⁺).

EXAMPLE 4-4N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N-methyl-1-butanesulfonamide

45 mg (0.32 mmol) of methyl iodide and 109 mg (0.79 mmol) of potassiumcarbonate are added to a solution of 30 mg (0.08 mmol) ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-1-butanesulfonamidein 2 ml of acetone. The mixture is stirred under reflux overnight. Thereaction mixture is then evaporated to dryness, and the residue ispartitioned between methylene chloride and water. The organic phase isdried over sodium sulfate and concentrated. The resulting residue isfractionated by preparative HPLC (column: Kromasil 120 ODS-4HE, 10 μm,250×20 mm; eluent: acetonitrile/water; flow rate: 25 ml/min; UVdetection at 210 nm). 9 mg (0.02 mmol, 29% yield) of the product areobtained as a colorless crystalline solid.

R_(f): 0.44 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 394 ([M+H]⁺).

EXAMPLE 4-5N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-N-methyi-3-pyridinesulfonamide

7 mg (0.02 mmol, 21% yield) of the product are obtained as a pale yellowmicrocrystalline solid from 30 mg (0.07 mmol) ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-3-pyridinesulfonamide,39 mg (0.28 mmol) of methyl iodide and 97 mg (0.70 mmol) of potassiumcarbonate in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-N-methyi-1-butanesulfonamide.

R_(f): 0.38 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 415.2 ([M+H]⁺).

EXAMPLE 4-6N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N,3-dimethylbenzenesulfonamide

24 mg (0.06 mmol, 47% yield) of the product are obtained as a colorlessmicrocrystalline solid from 50 mg (0.12 mmol) ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-3-methylbenzenesulfonamide,68 mg (0.48 mmol) of methyl iodide and 167 mg (1.21 mmol) of potassiumcarbonate in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N-methyl-1-butanesulfonamide.

R_(f): 0.46 (cyclohexane/ethyl acetate 20:1).

MS (ESI): 428.1 ([M+H]⁺).

EXAMPLE 4-72-Cyano-N-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N-methylbenzenesulfonamide

39 mg (0.09 mmol, 75% yield) of the product are obtained as a colorlessmicrocrystalline solid from 50 mg (0.12 mmol) of2-cyano-N-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-benzenesulfonamide,67 mg (0.47 mmol) of methyliodide and 98 mg (0.71 mmol) of potassiumcarbonate in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N-methyl-1-butanesulfonamide.

R_(f): 0.43 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.38 (d, 1H), 7.72 (m, 2H), 7.65 (m,2H), 7.50 (d, 1H), 7.13 (dd, 1H), 3.48 (s, 3H), 2.89 (m, 1H), 2.70 (dd,1H), 2.55-2.35 (m, 2H), 2.03 (m, 1H), 1.70 (m, 1H), 1.48-1.36 (m, 3H),0.99 (t, 3H).

MS (ESI): 439.2 ([M+H]⁺).

EXAMPLE 4-83-Cyano-N-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-N-methylbenzenesulfonamide

27 mg (0.06 mmol, 52% yield) of the product are obtained as a colorlessmicrocrystalline solid from 50 mg (0.12 mmol) of3-cyano-N-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-benzenesulfonamide,67 mg (0.47 mmol) of methyliodide and 98 mg (0.71 mmol) of potassiumcarbonate in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N-methyl-1-butanesulfonamide.

R_(f): 0.43 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.41 (d, 1H), 7.90 (m, 2H), 7.66 (m,1H), 7.60 (d, 1H), 7.38 (d, 1H), 7.08 (dd, 1H), 3.27 (s, 3H), 2.91 (m,1H), 2.72 (dd, 1H), 2.60-2.35 (m, 2H), 2.05 (m, 1H), 1.71 (m, 1H),1.47-1.34 (m, 3H), 0.99 (t, 3H).

MS (ESI): 439.1 ([M+H]⁺).

EXAMPLE 4-94-Cyano-N-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-N-methylbenzenesulfonamide

31 mg (0.07 mmol, 60% yield) of the product are obtained as a colorlessamorphous solid from 50 mg (0.12 mmol) of4-cyano-N-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-benzenesulfonamide,67 mg (0.47 mmol) of methyliodide and 163 mg (1.18 mmol) of potassiumcarbonate in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N-methyl-1-butanesulfonamide.

R_(f): 0.41 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.42 (d, 1H), 7.75 (d, 2H), 7.64 (d,2H), 7.36 (d, 1H), 7.11 (dd, 1H), 3.27 (s, 3H), 2.91 (m, 1H), 2.72 (dd,1H), 2.59-2.36 (m, 2H), 2.06 (m, 1H), 1.71 (m, 1H), 1.48-1.37 (m, 3H),1.00 (t, 3H).

MS (ESI): 439 ([M+H]⁺).

EXAMPLE 4-10N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-N-methyl-1-propanesulfonamide

8 mg (0.02 mmol, 15% yield) of the product are obtained as a colorlessmicrocrystalline solid from 50 mg (0.14 mmol) ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-1-propanesulfonamide,78 mg (0.55 mmol) of methyl iodide and 190 mg (1.38 mmol) of potassiumcarbonate in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N-methyl-1-butanesulfonamide.

R_(f): 0.29 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.48 (d, 1H), 7.56 (d, 1H), 7.45 (dd,1H), 3.40 (s, 3H), 3.00 (m, 2H), 2.91 (m, 1H), 2.71 (dd, 1H), 2.58-2.35(m, 2H), 2.06 (m, 1H), 1.82 (m, 2H), 1.71 (m, 1H), 1.48-1.36 (m, 3H),1.02.(t, 3H), 0.99 (t, 3H).

MS (ESI): 380 ([M+H]⁺).

EXAMPLE 4-11N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-N-methylcyclopropanesulfonamide

18 mg (0.05 mmol, 35% yield) of the product are obtained as a colorlessamorphous solid from 50 mg (0.14 mmol) ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)cyclopropanesulfonamide,78 mg (0.55 mmol) of methyl iodide and 190 mg (1.38 mmol) of potassiumcarbonate in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N-methyl-1-butanesulfonamide.

R_(f): 0.31 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 378 ([M+H]⁺).

EXAMPLE 4-12N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-4-methoxy-N-methylbenzenesulfonamide

14 mg (0.03 mmol, 27% yield) of the product are obtained as a colorlessamorphous solid from 50 mg (0.12 mmol) ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-4-methoxybenzenesulfonamide,67 mg (0.47 mmol) of methyl iodide and 160 mg (1.16 mmol) of potassiumcarbonate in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-N-methyl-1-butanesulfonamide.

R_(f): 0.45 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.44 (d, 1H), 7.57 (t, 1H), 7.42 (m,3H), 7.12 (dd, 1H), 3.26 (s, 3H), 2.92 (m, 1H), 2.72 (dd, 1H), 2.58-2.37(m, 2H), 2.07 (m, 1H), 1.72 (m, 1H), 1.48-1.37 (m, 3H), 1.01 (t, 3H).

MS (ESI): 443.9 ([M+H]⁺).

EXAMPLE 4-133-Chloro-N-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-N-methylbenzenesulfonamide

11 mg (0.02 mmol, 21% yield) of the product are obtained as a paleyellow microcrystalline solid from 50 mg (0.12 mmol) of3-chloro-N-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)benzenesulfonamide,65 mg (0.46 mmol) of methyl iodide and 159 mg (1.15 mmol) of potassiumcarbonate in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-N-methyl-1-butanesulfonamide.

R_(f): 0.41 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 448.0 ([M+H]⁺).

EXAMPLE 4-14N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N,2-dimethylbenzenesulfonamide

27 mg (0.06 mmol, 65% yield) of the product are obtained as a colorlessamorphous solid from 40 mg (0.10 mmol) ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-2-methylbenzenesulfonamide,55 mg (0.39 rmol) of methyl iodide and 134 mg (0.97 mmol) of potassiumcarbonate in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-N-methyl-1-butanesulfonamide.

R_(f): 0.48 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 428.1 ([M+H]⁺).

EXAMPLE 4-15N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-N,2,4-trimethylbenzenesulfonamide

37 mg (0.08 mmol, 71% yield) of the product are obtained as a colorlessamorphous solid from 50 mg (0.12 mmol) ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-2,4-dimethylbenzenesulfonamide,67mg (0.47rmmol) of methyl iodide and 162 mg (1.17 mmol) of potassiumcarbonate in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-N-methyl-1-butanesulfonamide.

R_(f): 0.46 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 442.4 ([M+H]⁺).

EXAMPLE 4-16N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N-methyl-3-nitrobenzenesulfonamide

20 mg (0.04 mmol, 48% yield) of the product are obtained as a colorlessamorphous solid from 40 mg (0.09 mmol) ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-3-nitrobenzenesulfonamide,51 mg (0.36 mmol) of methyl iodide and 124 mg (0.90 mmol) of potassiumcarbonate in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-N-methyl-1-butanesulfonamide.

R_(f): 0.48 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 459.2 ([M+H]⁺).

EXAMPLE 4-175-Chloro-N-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-N-methyl-2-thiophenesulfonamide

81 mg (0.18 mmol, 98% yield) of the product are obtained as a paleyellow microcrystalline solid from 80 mg (0.18 mmol) of5-chloro-N-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-2-thiophenesulfonamide,104 mg (0.73 mmol) of methyl iodide and 252 mg (1.82 mmol) of potassiumcarbonate in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-N-methyl-1-butanesulfonamide.

R_(f): 0.51 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 454 ([M+H]⁺).

EXAMPLE 4-183-Ethyl-6-(2-pyridinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

150 mg (0.46 mmol) of6-bromo-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one are introducedinto 3 ml of dimethylformamide under an argon atmosphere. 141 mg (0.56mmol) of bis(pinacolato)diboron, 137 mg (1.39 mmol) of potassium acetateand 10 mg (0.01 mmol) ofdichloro[bis(diphenylphosphino)ferrocenyl]palladium(II) as catalyst aresuccessively added to this solution, and the mixture is stirred at 70°C. for 4 h. Then 88 mg (0.56 mmol) of 2-bromopyridine, a further 10 mgof catalyst dissolved in 1 ml of dimethylformamide and 1 ml of 2M sodiumcarbonate solution are added to this solution, and the mixture isstirred at 70° C. overnight. After cooling, the solution is partitionedbetween ethyl acetate and water, and the organic phase is washed withwater and dried over sodium sulfate. The residue obtained afterconcentration is fractionated by preparative HPLC (column: Kromasil 120ODS-4 HE, 10 μm, 250×20 mm; eluent: acetonitrile/water; flow rate: 25ml/min; UV detection at 210 nm). 21 mg (0.06 mmol, 14% yield) of theproduct are obtained as a colorless crystalline solid.

R_(f): 0.62 (cyclohexane/ethyl acetate 2:1).

MS (ED): 321 (M⁺).

EXAMPLE 4-193-Ethyl-6-(2-pyriridinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

8 mg (0.02 mmol, 5% yield) of the product are obtained as a colorlessmnicrocrystalline solid from 150 mg (0.46 mmol) of6-bromo-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one, 141 mg (0.56mmol) of bis(pinacolato)diboron, 137 mg (1.39 mmol) of potassium acetateand 88 mg (0.56 mmol) of 2-bromopyrimidine in analogy to the synthesisof 3-ethyl-6-(2-pyridinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one.

R_(f): 0.41 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 323.2 ([M+H]⁺).

EXAMPLE 4-202-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)benzonitrile

72 mg (0.21 mmol, 25% yield) of the product are obtained as a colorlessmicrocrystalline solid from 150 mg (0.82 mmol) of 2-bromobenzonitrile,251 mg (0.99 mmol) of bis(pinacolato)diboron, 243 mg (2.47 mmol) ofpotassium acetate and 320 mg (0.99 mmol) of6-bromo-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one in analogy tothe synthesis of3-ethyl-6-(2-pyridinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one.

R_(f): 0.42 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 8.42 (d, 1H), 8.06 (d, 1H), 8.03 (d,1H), 7.86 (m, 1H), 7.70 (m, 3H), 2.70 (m, 2H), 2.49 (m, 2H, overlappedby DMSO signal), 1.99 (m, 1H), 1.70 (m, 1H), 1.48-1.28 (m, 3H), 0.95 (t,3H).

MS (EI): 345 (M⁺).

EXAMPLE 4-213-Ethyl-6-(6-methyl-3-pyridinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

19 mg (0.06 mmol, 23% yield) of the product are obtained as a paleyellow amorphous solid from 80 mg (0.25 mmol) of6-bromo-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one, 76 mg (0.30mmol) of bis(pinacolato)diboron, 73 mg (0.74 mmol) of potassium acetateand 52 mg (0.30 mmol) of 2-bromo-5-methylpyridine in analogy to thesynthesis of3-ethyl-6-(2-pyridinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one.

R_(f): 0.34 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 8.58 (d, 1H), 8.45 (d, 1H), 8.41 (d,1H), 8.25 (dd, 1H), 8.08 (d, 1H), 7.78 (dd, 1H), 2.69 (m, 2H), 2.44 (m,2H, overlapped by DMSO signal), 2.38 (s, 3H), 1.98 (m, 1H), 1.68 (m,1H), 1.46-1.25 (m, 3H), 0.94 (t, 3H).

MS (ED): 335 (M⁺).

EXAMPLE 4-223-Ethyl-6-(6-chloro-3-pyridinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

10 mg (0.03 mmol, 9% yield) of the product are obtained as a colorlessamorphous solid from 100 mg (0.31 mmol) of6-bromo-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one, 86 mg (0.34mmol) of bis(pinacolato)diboron, 91 mg (0.93 mmol) of potassium acetateand 71 mg (0.37 mmol) of 2-bromo-5-chloropyridine in analogy to thesynthesis of3-ethyl-6-(2-pyridinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one.

R_(f): 0.38 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 356 ([M+H]⁺).

EXAMPLE 4-233-Ethyl-6-(2-methoxyphenyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

100 mg (0.31 mmol) of6-bromo-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one are introducedinto 3 ml of dimethoxyethane under an argon atmosphere. 56 mg (0.37mmol) of 2-methoxyphenylboronic acid, 10 mg (0.01 mmol) ofdichloro[bis(triphenylphosphino)]palladium(II) as catalyst and 0.34 mlof 2M sodium carbonate solution are added successively to this solution,and the mixture is stirred at 90° C. for 2 h. After cooling, thesolution is filtered through silica and washed with ethyl acetate. Theresidue obtained after concentration is purified by columnchromatography (silica gel, methylene chloride-methylenechloride/methanol 800:1-20:1). 90 mg (0.26 mmol, 83% yield) of theproduct are obtained as a colorless crystalline solid.

R_(f): 0.60 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.50 (d, 1H), 7.65 (m, 2H), 7.36 (m,2H), 7.07 (d, 1H), 7.01 (d, 1H), 3.82 (s, 3H), 2.93 (dt, 1H), 2.71 (dd,1H), 2.62-2.36 (m, 2H), 2.06 (m, 1H), 1.70 (m, 1H), 1.48-1.36 (m, 3H),0.99 (t, 3H).

MS (EI): 350 (M⁺).

EXAMPLE 4-244-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)benzaldehyde

81 mg (0.23 mmol, 75% yield) of the product are obtained as a colorlesscrystalline solid from 100 mg (0.31 mmol) of6-bromo-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 56 mg (0.37mmol) of 4-formylphenylboronic acid in analogy to the synthesis of3-ethyl-6-(2-methoxyphenyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one.

R_(f): 0.52 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 10.10 (s, 1H), 8.60 (d, 1H), 8.00 (d,2H), 7.82 (d, 2H), 7.75 (d, 1H), 7.72 (dd, 1H). 2.96 (dt, 1H), 2.77 (dd,1H), 2.67-2.36 (m, 2H), 2.08 (m, 1H), 1.73 (m, 1H), 1.50-1.32 (m, 3H),1.03 (t, 3H).

MS (ESI): 349.2 ([M+H]⁺).

EXAMPLE 4-253-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)benzaldehyde

72 mg (0.21 mmol, 67% yield) of the product are obtained as a colorlesscrystalline solid from 100 mg (0.31 mmol) of6-bromo-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 56 mg (0.37mmol) of 3-formylphenylboronic acid in analogy to the synthesis of3-ethyl-6-(2-methoxyphenyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one.

R_(f): 0.54 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 10.12 (s, 1H), 8.59 (d, 1H), 8.16 (m,1H), 7.92 (m, 2H), 7.75-7.63 (m, 3H), 2.96 (dt, 1H), 2.75 (dd, 1H),2.62-2.39 (m, 2H), 2.06 (m, 1H), 1.72 (m, 1H), 1.50-1.37 (m, 3H), 1.00(t, 3H).

MS (ESI): 349.2 ([M+H]⁺).

EXAMPLE 4-265-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-2-thiophenecarbaldehyde

252 mg (0.71 mmol, 76% yield) of the product are obtained as a paleyellow crystalline solid from 300 mg (0.93 mmol) of6-bromo-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 173 mg (1.11mmol) of 5-formyl-2-thienylboronic acid in analogy to the synthesis of3-ethyl-6-(2-methoxyphenyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one.

R_(f): 0.38 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 9.94 (s, 1H), 8.55 (d, 1H), 7.79 (d,1H), 7.77 (d, 1H), 7.74 (dd, 1H), 7.54 (d, 1H), 2.94 (dt, 1H), 2.74 (dd,1H), 2.62-2.37 (m, 2H), 2.07 (m, 1H), 1.73 (m, 1H), 1.49-1.30 (m, 3H),1.01 (t, 3H).

MS (ESI): 354.9 ([M+H]⁺).

EXAMPLE 4-273-Ethyl-6-(4-hydroxyphenyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

100 mg (0.31 mmol) of3-ethyl-6-(4-methoxyphenyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one areintroduced into 20 ml of methylene chloride under an argon atmosphere.1.43 ml of a 1M boron tribromide solution in methylene chloride areslowly added to this solution while cooling in ice, and the mixture isstirred at room temperature for 3 h. Then, while cooling in ice, 3 ml ofmethanol are cautiously added to the solution. The residue obtainedafter concentration is dissolved in methylene chloride and washed withwater. Drying of the organic phase over sodium sulfate and concentrationresult in 90 mg (0.27 mmol, 94% yield) of the product as a pale yellowamorphous solid.

R_(f): 0.20 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.52 (d, 1H), 7.68 (dd, 1H), 7.64 (d,1H), 7.58 (d, 2H), 6.95 (d, 2H), 5.06 (s, 1H), 2.96 (dt, 1H), 2.74 (dd,1H), 2.65-2.35 (m, 2H), 2.07 (m, 1H), 1.72 (m, 1H), 1.51-1.36 (m, 3H),1.00 (t, 3H).

MS (EI): 336 (M⁺).

EXAMPLE 4-283-Ethyl-6-(3-hydroxyphenyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

510 mg (1.46 mmol) of3-ethyl-6-(3-methoxyphenyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one areintroduced into 40 ml of methylene chloride under an argon atmosphere. 5ml of a 1M boron tribromide solution in methylene chloride is slowlyadded to this solution while cooling in ice, and the mixture is stirredat room temperature for 3 h. Then, while cooling in ice, 8 ml ofmethanol are cautiously added to the solution. The residue obtainedafter concentration is dissolved in methylene chloride and washed withwater. Drying of the organic phase over sodium sulfate and concentrationresult in 440 mg (1.30 mmol, 90% yield) of the product as a pale yellowamorphous solid.

R_(f): 0.24 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.49 (d, 1H), 7.69 (d, 1H), 7.66 (dd,1H), 7.27 (d, 1H), 7.13 (m, 2H), 6.89 (m, 1H), 4.87 (s, 1H), 2.92 (dt,1H), 2.76 (dd, 1H), 2.60-2.38 (m, 2H), 2.08 (m, 1H), 1.73 (m, 1H),1.53-1.25 (m, 3H), 1.02 (t, 3H).

MS (ESI): 337.3 (M⁺).

EXAMPLE 4-293-Ethyl-6-[4-(4-morpholinylmethyl)phenyl]-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

30 mg (0.09 mmol) of4-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)benzaldehyde aredissolved in 5 ml of 1,2-dichloroethane under an argon atmosphere and,while stirring, 8 mg (0.09 mmol) of morpholine and 28 mg (0.13 mmol) ofsodium(triacetoxyborohydride) are added. After 1 h, 5 μl of glacialacetic acid are added to this solution, and the mixture is stirredovernight. This solution is then partitioned between methylene chlorideand saturated sodium bicarbonate solution, and the organic phase iswashed with water and dried over sodium sulfate. Concentration resultsin 32 mg (0.08 mmol, 85% yield) of the product as a colorless amorphoussolid.

R_(f): 0.19 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.56 (d, 1H), 7.68 (m, 2H), 7.62 (d,2H), 7.44 (d, 2H), 3.72 (t, 4H), 3.57 (s, 2H), 2.95 (dt, 1H), 2.76 (dd,1H), 2.66-2.35 (m+t, 6H), 2.07 (m, 1H), 1.72 (m, 1H), 1.52-1.36 (m, 3H),1.01 (t, 3H).

MS (ESI): 420.4 ([M+H]⁺).

EXAMPLE 4-30N-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-N-methyl-2-naphthalenesulfonamide

10 mg (0.02 mmol, 15% yield) of the product are obtained as a paleyellow microcrystalline solid from 58 mg (0.13 mmol) ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-2-naphthalenesulfonamide,75 mg (0.53 mmol) of methyl iodide and 183 mg (1.33 mmol) of potassiumcarbonate in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-N-methyl-1-butanesulfonamide.

R_(f): 0.56 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 464.5 ([M+H]⁺).

EXAMPLE 4-31N-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N-methyl-2-thiophenesulfonamide

23 mg (0.05 mmol, 82% yield) of the product are obtained as a paleyellow microcrystalline solid from 28 mg (0.07 mmol) ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-2-thiophenesulfonamide,40 mg (0.28 mmol) of methyl iodide and 95 mg (0.69 mmol) of potassiumcarbonate in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-N-methyl-1-butanesulfonamide.

R_(f): 0.53 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 420.4 ([M+H]⁺).

EXAMPLE 4-322-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N-methylsulfonamide

15 mg (0.03 mmol, 35% yield) of the product are obtained as a paleyellow solid from 39 mg (0.08 mmol) of2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)ethanesulfonamide,48 mg (0.34 mmol) of methyl iodide and 117 mg (0.85 mmol) of potassiumcarbonate in analogy to the synthesis ofN-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-N-methyl-1-butanesulfonamide.

R_(f): 0.41 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 511.2 ([M+H]⁺).

EXAMPLE 4-333,3-Dimethyl-6-(4-methyl-3-pyridinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

49 mg (0.15 mmol, 31% yield) of the product are obtained as a colorlesscrystalline solid from 150 mg (0.46 mmol) of6-bromo-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one, 142 mg(0.56 mmol) of bis(pinacolato)diboron, 136 mg (1.39 mmol) of potassiumacetate and 103 mg (0.60 mmol) of 3-bromo-4-methylpyridine in analogy tothe synthesis of3-ethyl-6-(2-pyridinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one.

R_(f): 0.48 (cyclohexane/ethyl acetate 2:1).

MS (ESD: 336 ([M+H]⁺).

EXAMPLE 4-346-(6-Methoxy-3-pyridinyl)-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

68 mg (0.19 mmol, 42% yield) of the product are obtained as a paleyellow crystalline solid from 150 mg (0.46 mmol) of6-bromo-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one, 142 mg(0.56 mmol) of bis(pinacolato)diboron, 136 mg (1.39 mmol) of potassiumacetate and 113 mg (0.60 mmol) of 3-bromo-6-methoxypyridine in analogyto the synthesis of3-ethyl-6-(2-pyridinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one.

R_(f): 0.42 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.58 (d, 1H), 8.45 (d, 1H), 7.84 (dd,1H), 7.63 (m, 2H), 6.86 (d, 1H), 4.01 (s, 3H), 2.73 (t, 2H), 2.49 (s,2H), 1.64 (t, 2H) 1.06 (s, 6H).

MS (ESI): 352 ([M+H]⁺).

EXAMPLE 4-356-(4-Methoxy-5-pyrimidinyl)-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

62 mg (0.18 mmol, 43% yield) of the product are obtained as a paleyellow crystalline solid from 132 mg (0.41 mmol) of6-bromo-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one, 124 mg(0.49 mmol) of bis(pinacolato)diboron, 119 mg (1.22 mmol) of potassiumacetate and 100 mg (0.53 mmol) of 3-bromo-4-methoxypyrimidine in analogyto the synthesis of3-ethyl-6-(2-pyridinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one.

R_(f): 0.22 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.80 (s, 1H), 8.58 (d, 1H), 8.53 (s,1H), 7.69 (d, 1H), 7.63 (dd, 1H), 4.07 (s, 3H), 2.73 (t, 2H), 2.49 (s,2H), 1.63 (t, 2H), 1.04 (s, 6H).

MS (ESI): 353 ([M+H]⁺).

EXAMPLE 4-363,3-Dimethyl-6-(5-methyl-3-pyridinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

37 mg (0.11 mmol, 24% yield) of the product are obtained as a colorlesscrystalline solid from 150 mg (0.46 mmol) of6-bromo-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one, 142 mg(0.56 mmol) of bis(pinacolato)diboron, 136 mg (1.39 mmol) of potassiumacetate and 102 mg (0.60 mmol) of 3-bromo-5-methylpyridine in analogy tothe synthesis of3-ethyl-6-(2-pyridinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one.

R_(f): 0.39 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 336 ([M+H]⁺).

EXAMPLE 4-376-(5-Acetyl-3-pyridinyl)-3,3-dimethyl-1,2,3,4-tettahydro-9H-thioxanthen-9-one

34 mg (0.09 mmol, 20% yield) of the product are obtained as a colorlesscrystalline solid from 150 mg (0.46 mmol) of6-bromo-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one, 142 mg(0.56 mmol) of bis(pinacolato)diboron, 136 mg (1.39 mmol) of potassiumacetate and 120 mg (0.60 mmol) of 3-bromo-5-acetylpyridine in analogy tothe synthesis of3-ethyl-6-(2-pyridinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one.

R_(f): 0.42 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 9.19 (d, 1H), 9.05 (d, 1H), 8.62 (d,1H), 8.47 (t, 1H), 7.71 (m, 2H), 2.77 (t, 2H), 2.72 (s, 3H), 2.51 (s,2H), 1.65 (t, 2H), 1.06 (s, 6H).

MS (ESI): 364 ([M+H]⁺).

EXAMPLE 4-38 Methyl5-(3,3-dimethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)nicotinate

104 mg (0.27 mmol, 59% yield) of the product are obtained as a colorlesscrystalline solid from 150 mg (0.46 mmol) of6-bromo-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one, 142 mg(0.56 mmol) of bis(pinacolato)diboron, 136 mg (1.39 mmol) of potassiumacetate and 130 mg (0.60 mmol) of methyl 3-bromonicotinate in analogy tothe synthesis of3-ethyl-6-(2-pyridinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one.

R_(f): 0.40 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 9.26 (d, 1H), 9.05 (d, 1H), 8.62 (d,1H), 8.58 (t, 1H), 7.72 (m, 2H), 4.01 (s, 3H), 2.75 (t, 2H), 2.51 (s,2H), 1.66 (t, 2H), 1.05 (s, 6H).

MS (ESI): 380 ([M+H]⁺).

EXAMPLE 4-396-(5,6-Dimethyl-3-pyridinyl)-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

61 mg (0.17 mmol, 38% yield) of the product areobtained as a colorlesscrystalline solid from 150 mg (0.46 mmol) of6-bromo-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one, 142 mg(0.56 mmol) of bis(pinacolato)diboron, 136 mg (1.39 mmol) of potassiumacetate and 112 mg (0.60 mmol) of 3-bromo-5,6-dimethylpyridine inanalogy to the synthesis of3-ethyl-6-(2-pyridinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one.

R_(f): 0.37 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 349 ([M]⁺).

EXAMPLE 4-406-(4,6-Dimethoxy-5-pyrimidinyl)-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

104 mg (0.27 mmol, 59% yield) of the product are obtained as a colorlesscrystalline solid from 150 mg (0.46 mmol) of6-bromo-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one, 142 mg(0.56 mmol) of bis(pinacolato)diboron, 136 mg (1.39 mmol) of potassiumacetate and 131 mg (0.60 mmol) of 3-bromo-4,6-dimethoxypyrimidine inanalogy to the synthesis of3-ethyl-6-(2-pyridinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one.

R_(f): 0.25 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.52 (d, 1H), 8.46 (s, 1H), 7.56 (d,1H), 7.50 (dd, 1H), 3.95 (s, 6H), 2.73 (t, 2H), 2.48 (s, 2H), 1.63 (t,2H), 1.03 (s, 6H).

MS (ESI): 383 ([M+H]⁺).

EXAMPLE 4-413-(3-Ethyl-9-oxo-2,3,4,9-tetrahydro-1-thioxanthen-6-yl)-2-thiophenecarbaldehyde

210 mg (0.59 mmol, 63% yield) of the product are obtained as a paleyellow crystalline solid from 300 mg (0.93 mmol) of6-bromo-3-ethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 173 mg (1.11mmol) of 2-formylthiophene-3-boronic acid in analogy to the synthesis of3-ethyl-6-(2-methoxyphenyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one.

R_(f): 0.41 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 355.2 ([M+H]⁺).

EXAMPLE 4-423,3-Dimethyl-6-(5-pyrinmidinyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

0.9 g (2.79 mmol, 90% yield) of the product is obtained as a colorlesscrystalline solid from 1.00 g (3.09 mmol) of6-bromo-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 1.02 g(4.95 mmol) of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidinewith additional use of potassium phosphate as base anddichloro[bis(diphenylphosphino)ferrocenyl]palladium(II) as catalyst inanalogy to the synthesis of3-ethyl-6-(2-methoxyphenyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one.

R_(f): 0.18 (cyclohexane/ethyl acetate 2:1).

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 9.29 (s, 1H), 9.02 (s, 2H), 8.65 (d,1H), 7.69 (m, 2H), 2.75 (t, 2H), 2.51 (s, 2H), 1.66 (t, 2H), 1.05 (s,6H).

MS (ESI): 323 ([M+H]⁺).

EXAMPLE 4-436-(4-Methoxy-3-pyridinyl)-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

60 mg (0.17 mmol, 22% yield) of the product are obtained as a colorlesssolid from 240 mg (0.75 mmol) of6-bromo-3,3-dimethyl-1,2,3,4-tetrahydro-9H-thioxanthen-9-one and 150 mg(0.98 mmol) of 4-methoxy-3-pyridineboronic acid in analogy to thesynthesis of3-ethyl-6-(2-methoxyphenyl)-1,2,3,4-tetrahydro-9H-thioxanthen-9-one.

R_(f): 0.38 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 351 ([M]⁺).

EXAMPLE 4-443-Ethyl-6-[5-(4-morpholinylmethyl)-2-thienyl]-1,2,3,4-tetrahydro-9H-thioxanthen-9-one

13 mg (0.03 mmol, 15% yield) of the product are obtained as a colorlesssolid from 71 mg (0.20 mmol) of5-(3-ethyl-9-oxo-2,3,4,9-tetrahydro-1H-thioxanthen-6-yl)-2-thiophenecarbaldehyde,19 mg (0.22 mmol) of morpholine, 63 mg (0.30 mmol) ofsodium(triacetoxyborohydride) and 20 μl of glacial acetic acid inanalogy to the synthesis of3-ethyl-6-[4-(4-morpholinylmethyl)phenyl]-1,2,3,4-tetrahydro-9H-thioxanthen-9-one.

R_(f): 0.21 (cyclohexane/ethyl acetate 2:1).

MS (ESI): 425 ([M]⁺).

1. A compound of the formula (I),

in which the radical R¹-A- is located at either of positions 2 or 3 ofthe thiochromenone ring, R¹ is (C₆-C₁₀)-aryl or 5- to 10-memberedheteroaryl, where aryl and heteroaryl are optionally substitutedidentically or differently by radicals selected from the group ofhalogen, formyl, carbamoyl, cyano, hydroxyl, trifluoromethoxy, nitro,—NR³R⁴, tetrazolyl, (C₁-C₆)-alkoxycarbonyl and optionally hydroxyl-,morpholinyl-, (C₁-C₆)-acyloxy- or halogen-substituted (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy, (C₁-C₆)-acyl and (C₁-C₆)-alkylthio, in which R³ and R⁴are, independently of one another, hydrogen, (C₁-C₆)-alkyl or(C₁-C₆)-acyl, is 3- to 12-membered carbocyclyl or 4- to 12-memberedheterocyclyl, where carbocyclyl and heterocyclyl are optionallysubstituted identically or differently by radicals selected from thegroup of (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₁-C₆)-acyl,(C₁-C₆)-alkoxycarbonyl or oxo, or is a group of the formula R⁵-E-, inwhich E is optionally unsaturated (C₁-C₁₀)-alkanediyl, and R⁵ ishydrogen, carbamoyl, halogen, hydroxyl, nitro, trifluoromethyl, amino,mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, (C₁-C₆)-alkoxy,(C₆-C₁₀)-aryl, 5- to 10-membered heteroaryl or 4- to 10-membered,optionally oxo- and/or (C₁-C₆)-alkyl-substituted, optionally benzo-fusedheterocyclyl, where aryl, heteroaryl and benzo in turn may besubstituted by radicals selected from the group of halogen, cyano,trifluoromethyl, trifluoromethoxy, nitro and (C₁-C₆)-alkyl, A is a bondor a group of the formula O, S, NR⁶, CO, SO, SO₂, SO₂—O, CO—NR⁷,SO₂—NR⁸, O—SO₂, NR⁹—CO, NR¹⁰—SO₂, NR¹¹—SO₂—O, NR¹²—SO₂—NR¹³ orNR¹⁴—CO—NR¹⁵, in which R⁶ R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵are (C₃-C₈)-cycloalkyl or optionally unsaturated (C₁-C₆)-alkyl which isoptionally substituted by hydroxyl, phenyl, (C₁-C₆)-alkoxy,(C₁-C₆)-alkoxycarbonyl or (C₃-C₈)-cycloalkyl, where phenyl in turn maybe substituted by halogen or (C₁-C₄)-alkyl, or in which R⁶, R⁷, R⁹, R¹⁰,R¹¹, R¹², R¹⁴ and R¹⁵ are hydrogen, or the radical R¹-A- is hydrogen oramino, R² is hydrogen, halogen or (C₁-C₆)-alkyl or (C₁-C₆)-alkoxy, wherealkyl and alkoxy are optionally substituted up to twice-identically ordifferently by radicals selected from the group of hydroxyl,(C₁-C₆)-alkoxy, mono- and di-(C₁-C₆)-alkylamino, and D is an optionallyfluorine-substituted, divalent hydrocarbon radical having 3 to 10 carbonatoms, and the salts, hydrates and/or solvates thereof, with theexception of2-chloro-6,7,8,9,10,10a-hexahydrocyclohepta[b]thio-chromen-11(5aH)-one.2. A compound of the formula (I) as claimed in claim 1, where theradical R¹-A- is located at position 3 of the thiochromenone ring, R¹ is(C₆-C₁₀)-aryl or 5- to 10-membered heteroaryl, where aryl and heteroarylare optionally substituted identically or differently up to twice byradicals selected from the group of halogen, formyl, cyano, hydroxyl,hydroxymethyl, (C₁-C₆)-alkyl, is 4- to 10-membered heterocyclyl, whereheterocyclyl are optionally substituted identically or differently byradicals selected from the group of (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,(C₁-C₆)-alkoxycarbonyl or oxo, A is a bond or a group of the formulaNR⁶, CO—NR⁷, SO₂—NR⁸ or NR⁹—CO, in which R⁶, R⁷, R⁸ and R⁹ areoptionally unsaturated (C₁-C₆)-alkyl which is optionally substituted upto twice, identically or differently, by hydroxyl or methoxy, or inwhich R⁶, R⁷ and R⁹ are hydrogen, R² is hydrogen, and D is a group ofthe formula (CH₂)_(m)—CR¹⁶R¹⁷—(CH₂)_(n), in which the total number ofcarbon atoms is 3 to 10, m and n are identical or different and are anatural number from the series 0 to 6, and R¹⁶ and R¹⁷ are identical ordifferent and are hydrogen or (C₁-C₆)-alkyl which is optionallysubstituted identically or differently by (C₃-C₅)-cycloalkyl or halogen,or CR¹⁶R¹⁷ is (C₃-C₆)-cycloalkane-1,1-diyl, and the salts, hydratesand/or solvates thereof.
 3. A compound of the formula (I) as claimed inclaim 1, where the radical R¹-A- is located at position 3 of thethiochromenone ring, R¹ is phenyl or 5- to 6-membered heteroaryl, wherephenyl and heteroaryl are optionally substituted identically ordifferently up to twice by radicals selected from the group of halogen,cyano, (C₁-C₃)-alkyl, is 5- to 7-membered heterocyclyl, whereheterocyclyl are optionally substituted identically or differently byradicals selected from the group of (C₁-C₃)-alkyl or Oxo, A is a bond ora group of the formula NR⁶, SO₂—NR⁸ or NR⁹—CO, in which R⁶, R⁸ and R⁹are optionally unsaturated (C₁-C₃)-alkyl which is optionally substitutedup to twice, identically or differently, by hydroxyl or methoxy, and inwhich R⁶, R⁸ and R⁹ are hydrogen, R² is hydrogen, and D is a group ofthe formula (CH₂)_(m)—CR¹⁶R¹⁷—(CH₂)_(n), in which the total number ofcarbon atoms is 3 to 6, m and n are identical or different and are anatural number from the series 0 to 2, and R¹⁶ and R¹⁷ are identical ordifferent and are hydrogen or (C₁-C₃)-alkyl, or CR¹⁶R¹⁷ is(C₃-C₆)-cycloalkane-1,1-diyl, and the salts, hydrates and/or solvatesthereof.
 4. A compound of the formula (I) as claimed in claim 1 for thetreatment and/or prophylaxis of diseases.
 5. A medicament comprising atleast one of the compounds of the formula (I) as claimed in any ofclaims 1 to 3 mixed with at least one pharmaceutically acceptable,essentially non-toxic carrier or excipient.
 6. The use of compounds ofthe formula (I) as claimed in any of claims 1 to 3 for producing amedicament for the treatment and/or prophylaxis of states of pain and/orneurodegeinerative disorders.